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Simple Summary: Breast cancer stem cells (BCSCs) are a small population of cells in breast cancer tumors, playing a putative role in the cancer's progression. BCSC biomarkers are associated with cells' enhanced growth, adhesion, migration, and invasion potential and are responsible for poor outcomes. Due to the vast heterogeneity of breast cancer signaling pathways and associated therapeutic targets, treatment strategies vary and depend on the molecular subtype of BC. Nevertheless, drugs affecting the Wnt, Notch, Hedgehog, PI3K/Akt/mTOR, and HER2 signaling pathways have been effectively applied in BCSC elimination strategies. The complexity of the characteristics of each molecular subtype of breast cancer, with an emphasis on the involvement of breast cancer stem cells in the development, metastasis, and recurrence of the tumor, requires greater understanding. Continuous updating of knowledge and the development of new therapies will allow the effective elimination of cancer cells and the rapid recovery of patients. Breast cancer is one of the most frequently detected malignancies worldwide. It is responsible for more than 15% of all death cases caused by cancer in women. Breast cancer is a heterogeneous disease representing various histological types, molecular characteristics, and clinical profiles. However, all breast cancers are organized in a hierarchy of heterogeneous cell populations, with a small proportion of cancer stem cells (breast cancer stem cells (BCSCs)) playing a putative role in cancer progression, and they are responsible for therapeutic failure. In different molecular subtypes of breast cancer, they present different characteristics, with specific marker profiles, prognoses, and treatments. Recent efforts have focused on tackling the Wnt, Notch, Hedgehog, PI3K/Akt/mTOR, and HER2 signaling pathways. Developing diagnostics and therapeutic strategies enables more efficient elimination of the tumor mass together with the stem cell population. Thus, the knowledge about appropriate therapeutic methods targeting both "normal" breast cancer cells and breast cancer stem cell subpopulations is crucial for success in cancer elimination. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer mortality. Treatment of HCC remains challenging, especially for those with advanced stages or those with postoperative recurrence. Molecular research of signaling pathways to afford new options of treatments is urgent. Moreover, among the various signaling pathways, the Sonic hedgehog (SHH) signaling pathway is implicated in multiple aspects of HCC, including cancer development, growth, invasiveness, recurrence, metastasis, the tumor microenvironment, and the maintenance of its cancer stem cells. The SHH signaling pathway also contributes to the resistance of HCC to chemotherapy, target therapy, and radiation therapy. This narrative review of the update studies reappraises the roles of SHH signaling in HCC. A deeper understanding of the SHH signaling pathway is crucial. It may provide more insights into the regulatory processes to establish novel treatments for HCC. HCC remains one of the leading causes of cancer-related death globally. The main challenges in treatments of hepatocellular carcinoma (HCC) primarily arise from high rates of postoperative recurrence and the limited efficacy in treating advanced-stage patients. Various signaling pathways involved in HCC have been reported. Among them, the Sonic hedgehog (SHH) signaling pathway is crucial. The presence of SHH ligands is identified in approximately 60% of HCC tumor tissues, including tumor nests. PTCH-1 and GLI-1 are detected in more than half of HCC tissues, while GLI-2 is found in over 84% of HCC tissues. The SHH signaling pathway (including canonical and non-canonical) is involved in different aspects of HCC, including hepatocarcinogenesis, tumor growth, tumor invasiveness, progression, and migration. The SHH signaling pathway also contributes to recurrence, metastasis, modulation of the cancer microenvironment, and sustaining cancer stem cells. It also affects the resistance of HCC cells to chemotherapy, target therapy, and radiotherapy. Reappraisal of the roles of the SHH signaling pathway in HCC may trigger some novel therapies for HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review paper, we outline the role of GLP-1-RAs in potentially influencing PCa development and progression. While GLP-1-RAs show promise in inhibiting cancer cell proliferation, particularly when combined with metformin or radiotherapy, clinical data on their impact on PCa outcomes are limited. Future research should focus on dedicated trials to evaluate GLP-1-RA's role in PCa management, including its potential as a prophylactic treatment and adjunct therapy in various PCa stages. Glucagon-like peptide-1 (GLP-1), an incretin hormone renowned for its role in post-meal blood sugar regulation and glucose-dependent insulin secretion, has gained attention as a novel treatment for diabetes through GLP-1 receptor agonists (GLP-1-RA). Despite their efficacy, concerns have been raised regarding the potential associations between GLP-1-RA and certain malignancies, including medullary thyroid cancer. However, evidence of its association with prostate cancer (PCa) remains inconclusive. This review delves into the intricate relationship between GLP-1-RA and PCa, exploring the mechanisms through which GLP-1-Rs may impact PCa cells. We discuss the potential pathways involving cAMP, ERK, AMPK, mTOR, and P27. Furthermore, we underscore the imperative for additional research to elucidate the impact of GLP-1-RA treatment on PCa progression, patient outcomes, and potential interactions with existing therapies. Translational studies and clinical trials are crucial for a comprehensive understanding of the role of GLP-1-RA in PCa management. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is the leading cause of death globally, prompting extensive research into drugs that can enhance survival rates. The aim of our review was to assess the potential of asiatic acid as an anticancer drug, or as a support for existing cancer therapies. In vitro and in vivo studies have shown that asiatic acid activates various molecular pathways and exerts multidirectional effects in an organism. It has been confirmed that metabolic pathways regulated by molecular targets, e.g., TNF-α, NF-κB, PI3K/Akt, VEGF, and others, are affected by asiatic acid and are crucial in tumorigenesis, proliferation, and metastasis. In cancer cells, asiatic acid can decrease gene expression, reduce phosphorylation, and induce apoptosis. The gathered evidence suggests that asiatic acid warrants further investigation as a potential anticancer drug or adjunctive therapy. Centella asiatica has been recognized for centuries in Eastern medicine for its pharmacological properties. Due to the increasing prevalence of oncological diseases worldwide, natural substances that could qualify as anticancer therapeutics are becoming increasingly important subjects of research. This review aims to find an innovative use for asiatic acid (AA) in the treatment or support of cancer therapy. It has been demonstrated that AA takes part in inhibiting phosphorylation, inducing cell death, and reducing tumor growth and metastasis by influencing important signaling pathways, such as PI3K, Akt, mTOR, p70S6K, and STAT3, in cancer cells. It is also worth mentioning the high importance of asiatic acid in reducing the expression of markers such as N-cadherin, β-catenin, claudin-1, and vimentin. Some studies have indicated the potential of asiatic acid to induce autophagy in cancer cells through changes in the levels of specific proteins such as LC3 and p62. It can also act as an anti-tumor immunotherapeutic agent, thanks to its inductive effect on Smad7 in combination with naringenin (an Smad3 inhibitor). It seems that asiatic acid may be a potential anticancer drug or form of adjunctive therapy. Further studies should take into account safety and toxicity issues, as well as limitations related to the pharmacokinetics of AA and its low oral bioavailability. [ABSTRACT FROM AUTHOR]

Simple Summary: Adrenocortical tumors are rare neoplasms with an uncertain prognosis. A greater understanding of the biology of these tumors will allow new therapeutic targets to be identified and the prognosis of these patients to be better understood, enabling more precise therapeutic targeting. Our study sought to evaluate the expression of the PRKAB2 gene as a prognostic biomarker in 63 cases of pediatric adrenocortical tumors and to analyze how efficient Rottlerin is in altering the tumorigenic profile of the NCI-H295R adrenocortical carcinoma (ACC) cell line. Pediatric adrenocortical tumors (ACTs) are rare, highly heterogeneous neoplasms with limited therapeutic options, making the investigation of new targets with potential therapeutic or prognostic purposes urgent. The PRKAB2 gene produces one of the subunits of the AMP-activated protein kinase (AMPK) complex and has been associated with cancer. However, little is known about the role AMPK plays in ACTs. We have evaluated how PRKAB2 is associated with clinical and biological characteristics in 63 pediatric patients with ACTs and conducted in vitro studies on the human NCI-H295R ACC cell line. An analysis of our cohort and the public ACC pediatric dataset GSE76019 showed that lower PRKAB2 expression was associated with relapse, death, metastasis, and lower event-free and overall survival rates. Multivariate analysis showed that PRKAB2 expression was an independent prognostic factor when associated with age, tumor weight and volume, and metastasis. In vitro tests on NCI-H295R cells demonstrated that Rottlerin, a drug that can activate AMPK, modulated several pathways in NCI-H295R cells, including AMPK/mTOR, Wnt/β-catenin, SKP2, HH, MAPK, NFKB, and TNF. Treatment with Rottlerin decreased cell proliferation and migration, clonogenic capacity, and steroid production. Together, these results suggest that PRKAB2 is a potential prognostic marker in pediatric ACTs, and that Rottlerin is promising for investigating drugs that can act against ACTs. [ABSTRACT FROM AUTHOR]

Simple Summary: The transcription factor RUNX family plays a crucial role in the formation of osteoblasts from bone marrow mesenchymal stem cells, contributing to bone development. However, emerging evidence suggests its involvement in tumor biology and cancer progression. In particular, the RUNX family has been associated with osteosarcoma by regulating factors related to tumorigenicity. As a vital molecule within the regulatory network of cancers, RUNX influences various upstream signaling pathways and downstream target molecules. Understanding the precise mechanisms underlying the development and prognosis of malignant tumors is essential. RUNX has been recognized as a potential therapeutic target for bone cancer, and further research into its role may lead to the development of new medications and improved clinical outcomes. The transcription factor runt-related protein (RUNX) family is the major transcription factor responsible for the formation of osteoblasts from bone marrow mesenchymal stem cells, which are involved in bone formation. Accumulating evidence implicates the RUNX family for its role in tumor biology and cancer progression. The RUNX family has been linked to osteosarcoma via its regulation of many tumorigenicity-related factors. In the regulatory network of cancers, with numerous upstream signaling pathways and its potential target molecules downstream, RUNX is a vital molecule. Hence, a pressing need exists to understand the precise process underpinning the occurrence and prognosis of several malignant tumors. Until recently, RUNX has been regarded as one of the therapeutic targets for bone cancer. Therefore, in this review, we have provided insights into various molecular mechanisms behind the tumorigenic role of RUNX in various important cancers. RUNX is anticipated to grow into a novel therapeutic target with the in-depth study of RUNX family-related regulatory processes, aid in the creation of new medications, and enhance clinical efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: The involvement of the renin-angiotensin pathway in both the regulation of the cardiovascular system and in tumorigenesis raises the question of the prognostic impact of renin-angiotensin system blockers (RABs) in cancer patients experiencing life-threatening complications. The aim of our retrospective study was to assess this impact in solid tumor patients requiring unplanned ICU admission over a 14-year period. Among 1845 patients mainly diagnosed with gastrointestinal and lung cancers, 414 (22.4%) were treated with RABs: 220 (53.1%) with angiotensin-receptor blockers (ARBs) and 194 (46.9%) with angiotensin-converting enzyme inhibitors (ACEis). ARBs use and ACEis use were both associated with improved in-ICU survival, whereas only ARBs use was associated with improved one-year survival. Increasing evidence argues for the promotion of tumorigenesis through activation of the renin-angiotensin system pathway. Accordingly, a benefit of renin-angiotensin system blockers (RABs) treatments has been suggested in patients with solid cancers in terms of survival. We aimed to evaluate in-ICU survival and one-year survival in cancer patients admitted to the ICU with respect to the use of RABs. We conducted a retrospective observational single-center study in a 24-bed medical ICU. We included all solid cancer patients (age ≥ 18 years) requiring unplanned ICU admission. From 2007 to 2020, 1845 patients with solid malignancies were admitted (median age 67 years (59–75), males 61.7%). The most frequent primary tumor sites were the gastrointestinal tract (26.8%), the lung (24.7%), the urological tract (20.1%), and gynecologic and breast cancers (13.9%). RABs were used in 414 patients, distributed into 220 (53.1%) with angiotensin-receptor blockers (ARBs) and 194 (46.9%) with angiotensin-converting enzyme inhibitors (ACEis). After multivariate adjustment, ARBs use (OR = 0.62, 95%CI (0.40–0.92), p = 0.03) and ACEis use (OR = 0.52, 95%CI (0.32–0.82), p = 0.006) were both associated with improved in-ICU survival. Treatment with ARBs was independently associated with decreased one-year mortality (OR = 0.6, 95%CI (0.4–0.9), p = 0.02), whereas treatment with ACEis was not. In conclusion, this study argues for a beneficial impact of RABs use on the prognosis of critically ill cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Solitary fibrous tumor (SFT) is a soft-tissue sarcoma occurring in adults and infants. This nonhereditary cancer is the result of an environmental intrachromosomal gene fusion between NAB2 and STAT6 on chromosome 12. Either surgery or radiation is the first line of treatment for this cancer; however for many, this becomes challenging, as the cancer can travel to inoperable areas or reoccur in locations already irradiated. Currently there is no approved chemotherapy regimen for SFTs. Anti-angiogenic drugs developed to treat other cancers have been used on SFTs with limited success. Therefore, there is a need for systemic therapy. In this study, we showed that RNA-targeting technologies (antisense oligonucleotides and CRISPR/CasRx) can be used to specifically suppress the expressions of NAB2–STAT6 fusion transcripts, but not wild type STAT6, and reduce cell proliferation and tumor growth. These results provide the foundation for a potentially novel therapeutical strategy for SFTs. Solitary fibrous tumor (SFT) is a rare soft-tissue sarcoma. This nonhereditary cancer is the result of an environmental intrachromosomal gene fusion between NAB2 and STAT6 on chromosome 12, which fuses the activation domain of STAT6 with the repression domain of NAB2. Currently there is not an approved chemotherapy regimen for SFTs. The best response on available pharmaceuticals is a partial response or stable disease for several months. The purpose of this study is to investigate the potential of RNA-based therapies for the treatment of SFTs. Specifically, in vitro SFT cell models were engineered to harbor the characteristic NAB2–STAT6 fusion using the CRISPR/SpCas9 system. Cell migration as well as multiple cancer-related signaling pathways were increased in the engineered cells as compared to the fusion-absent parent cells. The SFT cell models were then used for evaluating the targeting efficacies of NAB2–STAT6 fusion-specific antisense oligonucleotides (ASOs) and CRISPR/CasRx systems. Our results showed that fusion specific ASO treatments caused a 58% reduction in expression of fusion transcripts and a 22% reduction in cell proliferation after 72 h in vitro. Similarly, the AAV2-mediated CRISPR/CasRx system led to a 59% reduction in fusion transcript expressions in vitro, and a 55% reduction in xenograft growth after 29 days ex vivo. [ABSTRACT FROM AUTHOR]

Simple Summary: Salivary adenoid cystic carcinoma (SACC) is an aggressive tumor that exhibits a neurotropic growth pattern by invading nerve fibers and demonstrates a high tendency for both local spread and early distant metastases. The limited availability of successful chemotherapeutic regimens represents a major obstacle in the efficient treatment of SACC patients. Through epithelial–mesenchymal transition (EMT), cancer cells gain increased mobility and invasiveness, facilitating their ability to infiltrate the basement membrane and disseminate to distant sites in the body. This manuscript aims to review the latest research on potential biomarkers that contribute to the development of EMT, which can aid in identifying new therapeutic targets and improving the oncological management of SACC patients. Salivary adenoid cystic carcinoma (SACC) is considered a challenging malignancy; it is characterized by a slow-growing nature, yet a high risk of recurrence and distant metastasis, presenting significant hurdles in its treatment and management. At present, there are no approved targeted agents available for the management of SACC and systemic chemotherapy protocols that have demonstrated efficacy remain to be elucidated. Epithelial–mesenchymal transition (EMT) is a complex process that is closely associated with tumor progression and metastasis, enabling epithelial cells to acquire mesenchymal properties, including increased mobility and invasiveness. Several molecular signaling pathways have been implicated in the regulation of EMT in SACC, and understanding these mechanisms is crucial to identifying new therapeutic targets and developing more effective treatment approaches. This manuscript aims to provide a comprehensive overview of the latest research on the role of EMT in SACC, including the molecular pathways and biomarkers involved in EMT regulation. By highlighting the most recent findings, this review offers insights into potential new therapeutic strategies that could improve the management of SACC patients, especially those with recurrent or metastatic disease. [ABSTRACT FROM AUTHOR]

Simple Summary: This study was the first to demonstrate the anticancer effects of luteolin (Lut) combined with asiatic acid (AsA) on CaSki and HeLa cervical cancer cells. Lut combined with AsA effectively reduced cervical cancer cell viability by arresting the cell cycle in the sub-G1 phase and inducing caspase-mediated intrinsic apoptosis. Lut combined with AsA treatment downregulated PI3K/AKT signaling (PI3K, AKT and p70S6K), JNK/p38 MAPK signaling and FAK signaling (integrin β1, paxillin and FAK) and upregulated ERK signaling to induce apoptosis and inhibit cancer cell migration. In in vivo study, Lut combined with AsA markedly inhibited cervical cancer cell-derived xenograft tumor growth and the cytotoxic effect was minimal or nonexistent. Collectively, the present study demonstrated that Lut combined with AsA may be used as an anticancer agent in future clinical treatment to improve the prognosis of cervical cancer. Cervical cancer is an important issue globally because it is the second most common gynecological malignant tumor and conventional treatment effects have been shown to be limited. Lut and AsA are plant-derived natural flavonoid and triterpenoid products that have exhibited anticancer activities and can modulate various signaling pathways. Thus, the aim of the present study was to evaluate whether Lut combined with AsA could enhance the anticancer effect to inhibit cervical cancer cell proliferation and examine the underlying molecular mechanisms in vitro and in vivo. The results of a CCK-8 assay showed that Lut combined with AsA more effectively inhibited the proliferation of CaSki and HeLa cells than Lut or AsA treatment alone. Lut combined with AsA caused apoptosis induction and sub-G1-phase arrest in CaSki and HeLa cells, as confirmed by flow cytometry, mitoROS analysis, antioxidant activity measurement and western blot assay. In addition, Lut combined with AsA significantly inhibited the cell migration ability of CaSki and HeLa cells in a wound-healing assay. Furthermore, Lut combined with AsA induced apoptosis and inhibited migration through downregulated PI3K/AKT (PI3K, AKT and p70S6K), JNK/p38 MAPK and FAK (integrin β1, paxillin and FAK) signaling and upregulated ERK signaling. In an in vivo study, Lut combined with AsA markedly inhibited cervical cancer cell-derived xenograft tumor growth. Collectively, the present study showed that Lut combined with AsA may be used as an anticancer agent to improve the prognosis of cervical cancer. Indeed, with additional research to develop standardized dosages, Lut and AsA combination therapy could also be applied in clinical medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: Oral squamous cell carcinomas (OSCC) are the most common malignancies affecting the oral cavity and account for 40% of all head and neck squamous cell carcinoma cases. Unfortunately, patient outcomes are generally unfavorable, as diagnosis normally occurs at a late stage of the disease, as well as a lack of effective targeted treatments. Our identification of potential prognostic biomarkers is of particular importance to the field and could lead to the generation of effective targeted therapies which may improve patient outcomes and survival. Here, we utilize a mouse model of OSCC to explore the role of p63 as an important oncogenic transcription factor in the control of OSCC proliferation and migration. We also generate a p63-driven gene expression signature for mouse OSCC which identifies both novel and conserved genes and pathways, which may be relevant in human disease and which may serve as potential biomarkers and targets for future therapeutics. Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity and is linked to tobacco exposure, alcohol consumption, and human papillomavirus infection. Despite therapeutic advances, a lack of molecular understanding of disease etiology, and delayed diagnoses continue to negatively affect survival. The identification of oncogenic drivers and prognostic biomarkers by leveraging bulk and single-cell RNA-sequencing datasets of OSCC can lead to more targeted therapies and improved patient outcomes. However, the generation, analysis, and continued utilization of additional genetic and genomic tools are warranted. Tobacco-induced OSCC can be modeled in mice via 4-nitroquinoline 1-oxide (4NQO), which generates a spectrum of neoplastic lesions mimicking human OSCC and upregulates the oncogenic master transcription factor p63. Here, we molecularly characterized established mouse 4NQO treatment-derived OSCC cell lines and utilized RNA and chromatin immunoprecipitation-sequencing to uncover the global p63 gene regulatory and signaling network. We integrated our p63 datasets with published bulk and single-cell RNA-sequencing of mouse 4NQO-treated tongue and esophageal tumors, respectively, to generate a p63-driven gene signature that sheds new light on the role of p63 in murine OSCC. Our analyses reveal known and novel players, such as COTL1, that are regulated by p63 and influence various oncogenic processes, including metastasis. The identification of new sets of potential biomarkers and pathways, some of which are functionally conserved in human OSCC and can prognosticate patient survival, offers new avenues for future mechanistic studies. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of the present review was to summarize our studies on the signaling pathways in cancer types that are involved in the development of oral cancer and several mitogen-activated protein kinase-related molecular targeting technologies combined with immune checkpoint therapies to provide new therapeutic strategies for oral squamous cell carcinoma. In addition, we have provided a reasonable outlook, with a systematic basis, for future diagnosis and accurate treatment. Oral squamous cell carcinoma accounts for 95% of human head and neck squamous cell carcinoma cases. It is highly malignant and aggressive, with a poor prognosis and a 5-year survival rate of <50%. In recent years, basic and clinical studies have been performed on the role of the mitogen-activated protein kinase (MAPK) signaling pathway in oral cancer. The MAPK signaling pathway is activated in over 50% of human oral cancer cases. Herein, we review research progress on the MAPK signaling pathway and its potential therapeutic mechanisms and discuss its molecular targeting to explore its potential as a therapeutic strategy for oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: For tumors to initiate and sustain rapid growth, they need to alter their metabolic reprograming to support this growth. While many oncogenes upregulate metabolic pathways in cancer, here, we focus on how mutant p53 interacts with the mevalonate pathway (MVA) and functions as a continual on switch, causing tumor cells to grow uncontrollably. The relationship of mutant p53 and the MVA pathway in promoting tumorigenesis and the pleiotropic effects within the tumor microenvironment as a result of MVA pathway upregulation are discussed in this review. Many individuals are prescribed a statin drug to decrease their circulating cholesterol levels by blocking the MVA pathway. Several studies have suggested the potential of repurposing statins to treat various cancers, since tumor cells upregulate and rely substantially on the MVA pathway. We evaluate previous studies on statins and cancer incidence and patient mortality, as well as future research to optimize the use of statins as a cancer therapy. Tumor cells have the ability to co-opt multiple metabolic pathways, enhance glucose uptake and utilize aerobic glycolysis to promote tumorigenesis, which are characteristics constituting an emerging hallmark of cancer. Mutated tumor suppressor and proto-oncogenes are frequently responsible for enhanced metabolic pathway signaling. The link between mutant p53 and the mevalonate (MVA) pathway has been implicated in the advancement of various malignancies, with tumor cells relying heavily on increased MVA signaling to fuel their rapid growth, metastatic spread and development of therapy resistance. Statin drugs inhibit HMG-CoA reductase, the pathway's rate-limiting enzyme, and as such, have long been studied as a potential anti-cancer therapy. However, whether statins provide additional anti-cancer properties is worthy of debate. Here, we examine retrospective, prospective and pre-clinical studies involving the use of statins in various cancer types, as well as potential issues with statins' lack of efficacy observed in clinical trials and future considerations for upcoming clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian granulosa cell tumors are rare ovarian tumors, with poorly understood etiology. The aim of this study is to define the molecular changes in ovarian granulosa cell tumors. We used a granulosa cell tumor mouse model that contains dysregulated transforming growth factor β signaling. Using RNA-sequencing technology, we identified differentially expressed genes between tumor tissues and normal controls. In addition, comparative analyses have been performed to reveal common genes altered in ovarian granulosa cell tumors between the mouse and the human. This study has revealed the molecular signature of ovarian granulosa cell tumors in a mouse model. The results are potentially important to understand cell signaling events that regulate the development of a class of rare ovarian tumors. Ovarian granulosa cell tumors (GCTs) are rare sex cord-stromal tumors, accounting for ~5% ovarian tumors. The etiology of GCTs remains poorly defined. Genetically engineered mouse models are potentially valuable for understanding the pathogenesis of GCTs. Mice harboring constitutively active TGFβ signaling (TGFBR1-CA) develop ovarian GCTs that phenocopy several hormonal and molecular characteristics of human GCTs. To determine molecular alterations in the ovary upon TGFβ signaling activation, we performed transcriptomic profiling of gene expression associated with GCT development using ovaries from 1-month-old TGFBR1-CA mice and age-matched controls. RNA-sequencing and bioinformatics analysis coupled with the validation of select target genes revealed dysregulations of multiple cellular events and signaling molecules/pathways. The differentially expressed genes are enriched not only for known GCT-related pathways and tumorigenic events but also for signaling events potentially mediated by neuroactive ligand-receptor interaction, relaxin signaling, insulin signaling, and complements in TGFBR1-CA ovaries. Additionally, a comparative analysis of our data in mice with genes dysregulated in human GCTs or granulosa cells overexpressing a mutant FOXL2, the genetic hallmark of adult GCTs, identified some common genes altered in both conditions. In summary, this study has revealed the molecular signature of ovarian GCTs in a mouse model that harbors the constitutive activation of TGFBR1. The findings may be further exploited to understand the pathogenesis of a class of poorly defined ovarian tumors. [ABSTRACT FROM AUTHOR]

The AXL receptor tyrosine kinase (AXL) has emerged as a promising therapeutic target for cancer therapy. Recent studies have revealed a central role of AXL signaling in tumor proliferation, survival, stem cell phenotype, metastasis, and resistance to cancer therapy. Moreover, AXL is expressed within cellular components of the tumor microenvironment where AXL signaling contributes to the immunosuppressive and protumorigenic phenotypes. A variety of AXL inhibitors have been developed and are efficacious in preclinical studies. These agents offer new opportunities for therapeutic intervention in the prevention and treatment of advanced disease. Here we review the literature that has illuminated the cellular and molecular mechanisms by which AXL signaling promotes tumor progression and we will discuss the therapeutic potential of AXL inhibition for cancer therapy. [ABSTRACT FROM AUTHOR]

The Wnt signaling pathway is intricately involved in many aspects of development and is the root cause of an increasing number of diseases. For example, colorectal cancer is the second leading cause of death in the industrialized world and aberration of Wnt signaling within the colonic stem cell is the cause of more than 90% of these cancers. Despite our advances in successfully targeting other pathways, such as Human Epidermal Growth Factor Receptor 2 (HER2), there are no clinically relevant therapies available for Wnt-related diseases. Here, we investigated where research activities are focused with respect to Wnt signaling modulators by searching the United States Patent and Trade Office (USPTO) for patents and patent applications related to Wnt modulators and compared this to clinical trials focusing on Wnt modulation. We found that while the transition of intellectual property surrounding the Wnt ligand-receptor interface to clinical trials is robust, this is not true for specific inhibitors of β-catenin, which is constitutively active in many cancers. Considering the ubiquitous use of the synthetic T-cell Factor/Lymphoid Enhancer Factor (TCF/Lef) reporter system and its success in identifying novel modulators in vitro, we speculate that this model of drug discovery does not capture the complexity of in vivo Wnt signaling that may be required if we are to successfully target the Wnt pathway in the clinic. Notwithstanding, increasingly more complex models are being developed, which may not be high throughput, but more pragmatic in our pursuit to control Wnt signaling. [ABSTRACT FROM AUTHOR]

The wingless (Wnt) signaling is suggested as a fundamental hierarchical pathway in regulation of proliferation and differentiation of cells. The Wnt ligands are small proteins of about 40 kDa essentially for regulation and initiation of the Wnt activity. They are secreted proteins requiring acylation for activity in the Wnt signaling cascade and for functional interactivity with transmembrane proteins. Dual lipidation is important for posttranslational activation of the overwhelming number of Wnt proteins and is probably involved in their spatial distribution. The intestinal mucosa, where Wnt signaling is essential in configuration and maintenance, is an established model to study Wnt proteins and their role in carcinogenesis and cancer. The intestinal crypt-villus/crypt-plateau axis, a cellular system with self-renewal, proliferation, and differentiation, is tightly coordinated by a Wnt gradient. In the review, some attention is given to Wnt3, Wnt3A, and Wnt2B as important members of the Wnt family to address the role of lipidation and modifiers of Wnt proteins in intestinal carcinogenesis. Wnt3 is an important player in establishing the Wnt gradient in intestinal crypts and is mainly produced by Paneth cells. Wnt2B is characterized as a mitochondrial protein and shuttles between mitochondria and the nucleus. Porcupine and ACSL5, a long-chain fatty acid activating enzyme, are introduced as modifiers of Wnts and as interesting strategy to targeting Wnt-driven carcinogenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: Exogenous and endogenous estrogens and associated receptors modulate signaling pathways with biochemical events implicated in non-small cell lung cancer (NSCLC) manifestation. The diversity of biochemical interactions initiated by estrogens is rigorous, regulated via distinct estrogen-associated receptors. While estrogen receptor beta (ERβ) is overexpressed in 60–80% of NSCLCs irrespective of gender, the recognition of transmembrane G-protein-coupled estrogen receptor (GPER) creates several interfaces of estrogen-interception-driven aggressive NSCLC manifestation. There is still room for understanding the crux of ER–EGFR (epidermal growth factor receptor) interactions considering the recent clinical trials revealing a synergistic anti-NSCLC response. With such insights, this manuscript presents a comprehensive discussion on the sequential biochemical events in estrogen-activated cell signaling pathways in NSCLC complications with a focus on the ER/GPER/EGFR/ERR regulatory mechanism alongside the NSCLC treating anti-estrogen targeted therapies. Non-small cell lung cancers (NSCLCs) account for ~85% of lung cancer cases worldwide. Mammalian lungs are exposed to both endogenous and exogenous estrogens. The expression of estrogen receptors (ERs) in lung cancer cells has evoked the necessity to evaluate the role of estrogens in the disease progression. Estrogens, specifically 17β-estradiol, promote maturation of several tissue types including lungs. Recent epidemiologic data indicate that women have a higher risk of lung adenocarcinoma, a type of NSCLC, when compared to men, independent of smoking status. Besides ERs, pulmonary tissues both in healthy physiology and in NSCLCs also express G-protein-coupled ERs (GPERs), epidermal growth factor receptor (EGFRs), estrogen-related receptors (ERRs) and orphan nuclear receptors. Premenopausal females between the ages of 15 and 50 years synthesize a large contingent of estrogens and are at a greater risk of developing NSCLCs. Estrogen—ER/GPER/EGFR/ERR—mediated activation of various cell signaling molecules regulates NSCLC cell proliferation, survival and apoptosis. This article sheds light on the most recent achievements in the elucidation of sequential biochemical events in estrogen-activated cell signaling pathways involved in NSCLC severity with insight into the mechanism of regulation by ERs/GPERs/EGFRs/ERRs. It further discusses the success of anti-estrogen therapies against NSCLCs. [ABSTRACT FROM AUTHOR]

Simple Summary: Osteosarcoma is highly variable and heterogeneous, which is one of the reasons for its resistance to treatment. Because osteosarcoma is defined by abnormal bone formation, we hypothesize its suppression could lead to effective treatment for all types of osteosarcomas. Sclerostin is secreted by osteocytes and inhibits the canonical pathway by binding to LRP5/6, thereby suppressing bone formation. The resulting suppression of bone formation leads to bone loss and osteoporosis. Here, we investigated the antitumor effect of sclerostin against osteosarcoma and found that sclerostin suppressed the proliferative capacity and migratory ability of osteosarcoma cells. Various risk factors and causative genes of osteosarcoma have been reported in the literature; however, its etiology remains largely unknown. Bone formation is a shared phenomenon in all types of osteosarcomas, and sclerostin is an extracellular soluble factor secreted by osteocytes that prevents bone formation by inhibiting the Wnt signaling pathway. We aimed to investigate the antitumor effect of sclerostin against osteosarcoma. Osteosarcoma model mice were prepared by transplantation into the dorsal region of C3H/He and BALB/c-nu/nu mice using osteosarcoma cell lines LM8 (murine) and 143B (human), respectively. Cell proliferations were evaluated by using alamarBlue and scratch assays. The migratory ability of the cells was evaluated using a migration assay. Sclerostin was injected intraperitoneally for 7 days to examine the suppression of tumor size and extension of survival. The administration of sclerostin to osteosarcoma cells significantly inhibited the growth and migratory ability of osteosarcoma cells. Kaplan–Meier curves and survival data demonstrated that sclerostin significantly inhibited tumor growth and improved survival. Sclerostin suppressed the proliferative capacity and migratory ability of osteosarcoma cells. Osteosarcoma model mice inhibited tumor growth and prolonged survival periods by the administration of sclerostin. The effect of existing anticancer drugs such as doxorubicin should be investigated for future clinical applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Changes in the expression of key molecules such as microRNAs (miRs) can drive or suppress carcinogenesis and metastasis. A number of established transcriptional and genetic mechanisms regulate miR gene expression, but methylation/epigenetics have been analyzed less. Here, we systematically evaluated genome-wide methylation changes, focusing on miR, downstream targets, and further genes relevant for metastasis in colorectal cancers (CRC), including CpG islands, open seas, and north and south shore regions. A number of miRs deregulated during CRC progression/metastasis were significantly affected by methylation changes, especially within CpG islands and open seas. Several of these miRs cooperate in cancer- and metastasis-related pathways, while methylation changes otherwise primarily affect protein-coding genes. Our results highlight alternative routes to the transcriptional and genetic control of miR and further gene expression relevant for CRC progression and metastasis by changes in gene methylation. They also bear important therapeutic implications since drugs that alter methylation states are now in clinical use. MiRs are important players in cancer and primarily genetic/transcriptional means of regulating their gene expression are known. However, epigenetic changes modify gene expression significantly. Here, we evaluated genome-wide methylation changes focusing on miR genes from primary CRC and corresponding normal tissues. Differentially methylated CpGs spanning CpG islands, open seas, and north and south shore regions were evaluated, with the largest number of changes observed within open seas and islands. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed several of these miRs to act in important cancer-related pathways, including phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) pathways. We found 18 miR genes to be significantly differentially methylated, with MIR124-2, MIR124-3, MIR129-2, MIR137, MIR34B, MIR34C, MIR548G, MIR762, and MIR9-3 hypermethylated and MIR1204, MIR17, MIR17HG, MIR18A, MIR19A, MIR19B1, MIR20A, MIR548F5, and MIR548I4 hypomethylated in CRC tumor compared with normal tissue, most of these miRs having been shown to regulate steps of metastasis. Generally, methylation changes were distributed evenly across all chromosomes with predominance for chromosomes 1/2 and protein-coding genes. Interestingly, chromosomes abundantly affected by methylation changes globally were rarely affected by methylation changes within miR genes. Our findings support additional mechanisms of methylation changes affecting (miR) genes that orchestrate CRC progression and metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: The WNT/β-catenin signaling pathway is involved in fundamental processes for the proliferation and differentiation of mesenchymal stem cells. However, little is known about its relevance for mesenchymal neoplasms, such us soft tissue sarcomas (STS). Chemotherapy based on doxorubicin (DXR) still remains the standard first-line treatment for locally advanced unresectable or metastatic STS, although overall survival could not be improved by combination with other chemotherapeutics. In this sense, the development of new therapeutic approaches continues to be an unmatched goal. This review covers the most important molecular alterations of the WNT signaling pathway in STS, broadening the current knowledge about STS as well as identifying novel drug targets. Furthermore, the current therapeutic options and drug candidates to modulate WNT signaling, which are usually classified by their interaction site upstream or downstream of β-catenin, and their presumable clinical impact on STS are discussed. Soft tissue sarcomas (STS) are a very heterogeneous group of rare tumors, comprising more than 50 different histological subtypes that originate from mesenchymal tissue. Despite their heterogeneity, chemotherapy based on doxorubicin (DXR) has been in use for forty years now and remains the standard first-line treatment for locally advanced unresectable or metastatic STS, although overall survival could not be improved by combination with other chemotherapeutics. In this sense, the development of new therapeutic approaches continues to be a largely unmatched goal. The WNT/β-catenin signaling pathway is involved in various fundamental processes for embryogenic development, including the proliferation and differentiation of mesenchymal stem cells. Although the role of this pathway has been widely researched in neoplasms of epithelial origin, little is known about its relevance for mesenchymal neoplasms. This review covers the most important molecular alterations of the WNT signaling pathway in STS. The detection of these alterations and the understanding of their functional consequences for those pathways controlling sarcomagenesis development and progression are crucial to broaden the current knowledge about STS as well as to identify novel drug targets. In this regard, the current therapeutic options and drug candidates to modulate WNT signaling, which are usually classified by their interaction site upstream or downstream of β-catenin, and their presumable clinical impact on STS are also discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: PD-L1 is an important immune checkpoint molecule that is expressed in cancer tissues at various levels and plays a major role in tumor evasion from immune system. Therefore, understanding the mechanisms by which PD-L1 expression is regulated in tumor environment is important for the design of new therapeutic strategies to overcome tumor immune escape and improve the outcome of cancer treatment. Recent studies suggest that genetic, epigenetic, and transcriptional factors as well as posttranscriptional and posttranslational processes are crucial regulators of PD-L1 expression in tumor cells. This review focuses on two newly described regulations of PD-L1 mediated by oncogenes, and redox homeostasis. In this context, a recent research work describes the important role of oncogenic K-ras, growth factor receptors (FGFR1 and EGFR) and ROS in regulating PD-L1 expression in pancreatic cancer cells and aids significant new mechanistic insights in this important area. Tumor cells can evade the immune system via multiple mechanisms, including the dysregulation of the immune checkpoint signaling. These signaling molecules are important factors that can either stimulate or inhibit tumor immune response. Under normal physiological conditions, the interaction between programmed cell death ligand 1 (PD-L1) and its receptor, programmed cell death 1 (PD-1), negatively regulates T cell function. In cancer cells, high expression of PD-L1 plays a key role in cancer evasion of the immune surveillance and seems to be correlated with clinical response to immunotherapy. As such, it is important to understand various mechanisms by which PD-L1 is regulated. In this review article, we provide an up-to-date review of the different mechanisms that regulate PD-L1 expression in cancer. We will focus on the roles of oncogenic signals (c-Myc, EML4-ALK, K-ras and p53 mutants), growth factor receptors (EGFR and FGFR), and redox signaling in the regulation of PD-L1 expression and discuss their clinical relevance and therapeutic implications. These oncogenic signalings have common and distinct regulatory mechanisms and can also cooperatively control tumor PD-L1 expression. Finally, strategies to target PD-L1 expression in tumor microenvironment including combination therapies will be also discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: Oral squamous cell carcinoma (OSCC) accounts for the most malignancies. A GLO-BOCAN 2020 report estimated 377,713 new cases of oral cancer and 177,757 deaths due to oral cancer in 2020. Chrysosplenol D, a flavonol isolated from Artemisia annua L., can exert an-ticancer effects. This study investigated the anticancer property of chrysosplenol D and its un-derlying mechanism in oral squamous cell carcinoma. We observed that chrysosplenol D reduced cell viability, cell cycle arrest, apoptosis and autophagy in OSCC. Moreover, the upregulation of heme oxygenase-1 (HO-1) was found to be critical for chrysosplenol D-induced apoptotic cell death that patients with head and neck cancer had lower HO-1 expression. The findings of the present study indicated that chrysosplenol D exerts anticancer effects on OSCC by suppressing the MAPK pathway and activating HO-1 expression. Suggest that chrysosplenol D might be a potential anticancer agent for treating OSCC. Chrysosplenol D, a flavonol isolated from Artemisia annua L., can exert anticancer effects. This study investigated the anticancer property of chrysosplenol D and its underlying mechanism in oral squamous cell carcinoma (OSCC). We observed that chrysosplenol D reduced cell viability and caused cell cycle arrest in the G2/M phase. The findings of annexin V/propidium iodide staining, chromatin condensation, and apoptotic-related protein expression revealed that chrysosplenol D regulated apoptosis in OSCC. Furthermore, chrysosplenol D altered the expression of the autophagy marker LC3 and other autophagy-related proteins. Phosphatidylinositol 3-kinase/protein kinase B, extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase (MAPK) were downregulated by chrysosplenol D, and the inhibition of these pathways significantly enhanced chrysosplenol D-induced cleaved poly (ADP-ribose) polymerase activation. Moreover, the upregulation of heme oxygenase-1 (HO-1) was found to be critical for chrysosplenol D-induced apoptotic cell death. The analysis of clinical data from The Cancer Genome Atlas and Gene Expression Omnibus datasets revealed that patients with head and neck cancer had lower HO-1 expression than did those with no head and neck cancer. The findings of the present study indicated that chrysosplenol D exerts anticancer effects on OSCC by suppressing the MAPK pathway and activating HO-1 expression. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic melanoma is one of the most aggressive and lethal malignancies with a poor prognosis. Several data underline the crucial role of amoeboid motility in the dissemination of metastatic melanoma cells. Thus, targeting this phenomenon could represent a promising strategy to prevent metastasis formation and improve metastatic melanoma patient's survival. With this aim, we investigated the effect of Claisened Hexafluoro, a chemical analogue of Honokiol, on human metastatic melanoma cells. We demonstrated that Claisened Hexafluoro, by deregulating the mitochondrial activity, inhibits amoeboid motility and impairs many steps of the dissemination process, finally decreasing the in vivo metastatic spreading. Collectively, these data suggest possible future applications of Claisened Hexafluoro for the treatment of metastatic melanoma. Metastatic melanoma is characterized by poor prognosis and a low free-survival rate. Thanks to their high plasticity, melanoma cells are able to migrate exploiting different cell motility strategies, such as the rounded/amoeboid-type motility and the elongated/mesenchymal-type motility. In particular, the amoeboid motility strongly contributes to the dissemination of highly invasive melanoma cells and no treatment targeting this process is currently available for clinical application. Here, we tested Claisened Hexafluoro as a novel inhibitor of the amoeboid motility. Reported data demonstrate that Claisened Hexafluoro specifically inhibits melanoma cells moving through amoeboid motility by deregulating mitochondrial activity and activating the AMPK signaling. Moreover, Claisened Hexafluoro is able to interfere with the adhesion abilities and the stemness features of melanoma cells, thus decreasing the in vivo metastatic process. This evidence may contribute to pave the way for future possible therapeutic applications of Claisened Hexafluoro to counteract metastatic melanoma dissemination. [ABSTRACT FROM AUTHOR]

Simple Summary: In 2020, the global cancer database GLOBOCAN estimated 19.3 million new cancer cases worldwide. The discovery of targeted therapies may help prognosis and outcome of the patients affected, but the understanding of the plethora of highly interconnected pathways that modulate cell transformation, proliferation, invasion, migration and survival remains an ambitious goal. Here we propose an updated state of the art of YAP as the key protein driving oncogenic response via promoting all those steps at multiple levels. Of interest, the role of YAP in immunosuppression is a field of evolving research and growing interest and this summary about the current pharmacological therapies impacting YAP serves as starting point for future studies. Yes-associated protein (YAP) has emerged as a key component in cancer signaling and is considered a potent oncogene. As such, nuclear YAP participates in complex and only partially understood molecular cascades that are responsible for the oncogenic response by regulating multiple processes, including cell transformation, tumor growth, migration, and metastasis, and by acting as an important mediator of immune and cancer cell interactions. YAP is finely regulated at multiple levels, and its localization in cells in terms of cytoplasm–nucleus shuttling (and vice versa) sheds light on interesting novel anticancer treatment opportunities and putative unconventional functions of the protein when retained in the cytosol. This review aims to summarize and present the state of the art knowledge about the role of YAP in cancer signaling, first focusing on how YAP differs from WW domain-containing transcription regulator 1 (WWTR1, also named as TAZ) and which upstream factors regulate it; then, this review focuses on the role of YAP in different cancer stages and in the crosstalk between immune and cancer cells as well as growing translational strategies derived from its inhibitory and synergistic effects with existing chemo-, immuno- and radiotherapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Wnt has diverse regulatory roles at multiple cellular levels and numerous targeting points, and aberrant Wnt signaling has crucial roles in carcinogenesis, metastasis, cancer recurrence, and chemotherapy resistance; based on these facts, Wnt represents an appealing therapeutic target for cancer treatment. Although preclinical data supports a role for the Wnt signaling pathway in uterine carcinogenesis, this area remains understudied. In this review, we identify the functions of several oncogenes of the Wnt/β-catenin signaling pathway in tumorigenesis and address the translation approach with potent Wnt inhibitors that have already been established or are being investigated to target key components of the pathway. Further research is likely to expand the potential for both biomarker and cancer drug development. There is a scarcity of treatment choices for advanced and recurrent endometrial cancer; investigating the sophisticated connections of Wnt signaling networks in endometrial cancer could address the unmet need for new therapeutic targets. This review presents new findings on Wnt signaling in endometrial carcinoma and implications for possible future treatments. The Wnt proteins are essential mediators in cell signaling during vertebrate embryo development. Recent biochemical and genetic studies have provided significant insight into Wnt signaling, in particular in cell cycle regulation, inflammation, and cancer. The role of Wnt signaling is well established in gastrointestinal and breast cancers, but its function in gynecologic cancers, especially in endometrial cancers, has not been well elucidated. Development of a subset of endometrial carcinomas has been attributed to activation of the APC/β-catenin signaling pathway (due to β-catenin mutations) and downregulation of Wnt antagonists by epigenetic silencing. The Wnt pathway also appears to be linked to estrogen and progesterone, and new findings implicate it in mTOR and Hedgehog signaling. Therapeutic interference of Wnt signaling remains a significant challenge. Herein, we discuss the Wnt-activating mechanisms in endometrial cancer and review the current advances and challenges in drug discovery. [ABSTRACT FROM AUTHOR]

Simple Summary: Since it was first described over two decades ago, the Alternative Lengthening of Telomeres (ALT) pathway has been well accepted to hold clinical significance in cancer development, cancer diagnosis, and cancer treatment. In this review, first, we discuss how the activation of this pathway is determined. Then, we provide up-to-date statistics on the cancers ALT activity is detected in. We discuss the relationships between ALT positivity and prognosis as well as the pathogenetics of ALT positive cancers. Finally, we evaluate pre-clinical and clinical investigations of potential therapies targeting ALT. Many exciting advances in cancer-related telomere biology have been made in the past decade. Of these recent advances, great progress has also been made with respect to the Alternative Lengthening of Telomeres (ALT) pathway. Along with a better understanding of the molecular mechanism of this unique telomere maintenance pathway, many studies have also evaluated ALT activity in various cancer subtypes. We first briefly review and assess a variety of commonly used ALT biomarkers. Then, we provide both an update on ALT-positive (ALT+) tumor prevalence as well as a systematic clinical assessment of the presently studied ALT+ malignancies. Additionally, we discuss the pathogenetic alterations in ALT+ cancers, for example, the mutation status of ATRX and DAXX, and their correlations with the activation of the ALT pathway. Finally, we highlight important ALT+ clinical associations within each cancer subtype and subdivisions within, as well as their prognoses. We hope this alternative perspective will allow scientists, clinicians, and drug developers to have greater insight into the ALT cancers so that together, we may develop more efficacious treatments and improved management strategies to meet the urgent needs of cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a major public health problem worldwide, and addressing its morbidity, mortality, and prevalence is the first step towards appropriate control measures. Over the past several decades, many pharmacologists have worked to identify anti-cancer targets and drug development strategies. Within this timeframe, many natural compounds have been developed to inhibit cancer growth by targeting kinases, such as AKT, AURKA, and TOPK. Kinase assays and computer modeling are considered to be effective and powerful tools for target screening, as they can predict physical interactions between small molecules and their bio-molecular targets. In the present review, we summarize the inhibitors and compounds that target TOPK and describe its role in cancer progression. The extensive body of research that has investigated the contribution of TOPK to cancer suggests that it may be a promising target for cancer therapy. T-lymphokine-activated killer cell-originated protein kinase (TOPK, also known as PDZ-binding kinase or PBK) plays a crucial role in cell cycle regulation and mitotic progression. Abnormal overexpression or activation of TOPK has been observed in many cancers, including colorectal cancer, triple-negative breast cancer, and melanoma, and it is associated with increased development, dissemination, and poor clinical outcomes and prognosis in cancer. Moreover, TOPK phosphorylates p38, JNK, ERK, and AKT, which are involved in many cellular functions, and participates in the activation of multiple signaling pathways related to MAPK, PI3K/PTEN/AKT, and NOTCH1; thus, the direct or indirect interactions of TOPK make it a highly attractive yet elusive target for cancer therapy. Small molecule inhibitors targeting TOPK have shown great therapeutic potential in the treatment of cancer both in vitro and in vivo, even in combination with chemotherapy or radiotherapy. Therefore, targeting TOPK could be an important approach for cancer prevention and therapy. Thus, the purpose of the present review was to consider and analyze the role of TOPK as a drug target in cancer therapy and describe the recent findings related to its role in tumor development. Moreover, this review provides an overview of the current progress in the discovery and development of TOPK inhibitors, considering future clinical applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Microorganisms are found in all human tissues. Some of them are responsible for cancer formation. In our study we found gene expression from bacteria, archaea, and viruses in the upper female genital tract and this expression was associated with ovarian and endometrial cancer. We also found that the expression from these organisms may be involved in regulatory mechanisms of infection and cancer formation. Some of the processes associated with these organisms may affect cancer heterogeneity and be potential targets for cancer therapy. Bacteria, archaea, and viruses are associated with numerous human cancers. To date, microbiome variations in transcription have not been evaluated relative to upper female genital tract cancer risk. Our aim was to assess differences in bacterial, archaea, and viral transcript (BAVT) expression between different gynecological cancers and normal fallopian tubes. In this case-control study we performed RNA sequencing on 12 normal tubes, 112 serous ovarian cancers (HGSC) and 62 endometrioid endometrial cancers (EEC). We used the centrifuge algorithm to classify resultant transcripts into four indexes: bacterial, archaea, viral, and human genomes. We then compared BAVT expression from normal samples, HGSC and EEC. T-test was used for univariate comparisons (correcting for multiple comparison) and lasso for multivariate modelling. For validation we performed DNA sequencing of normal tubes in comparison to HGSC and EEC BAVTs in the TCGA database. Pathway analyses were carried out to evaluate the function of significant BAVTs. Our results show that BAVT expression levels vary between different gynecological cancers. Finally, we mapped some of these BAVTs to the human genome. Numerous map locations were close to regulatory genes and long non-coding RNAs based on the pathway enrichment analysis. BAVTs may affect gynecological cancer risk and may be part of potential targets for cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: REarranged during Transfection (RET) is an emerging target for several types of cancer, including non-small cell lung cancer (NSCLC). The recent U.S. FDA approval of pralsetinib and selpercatinib raises issues regarding the emergence of secondary mutations and amplifications involved in parallel signaling pathways and receptors, liable for resistance mechanisms. The aim of this review is to explore recent knowledge on RET resistance in NSCLC in pre-clinic and in clinical settings and accordingly, the state-of-the-art in new drugs or combination of drugs development. The potent, RET-selective tyrosine kinase inhibitors (TKIs) pralsetinib and selpercatinib, are effective against the RET V804L/M gatekeeper mutants, however, adaptive mutations that cause resistance at the solvent front RET G810 residue have been found, pointing to the need for the development of the next-generation of RET-specific TKIs. Also, as seen in EGFR- and ALK-driven NSCLC, the rising of the co-occurring amplifications of KRAS and MET could represent other escaping mechanisms from direct inhibition. In this review, we summarize actual knowledge on RET fusions, focusing on those involved in NSCLC, the results of main clinical trials of approved RET-inhibition drugs, with particular attention on recent published results of selective TKIs, and finally, pre-clinical evidence regarding resistance mechanisms and suggestion on hypothetical and feasible drugs combinations and strategies viable in the near future. [ABSTRACT FROM AUTHOR]

Simple Summary: In-time diagnosing ovarian cancer, intractable cancer that has no symptoms can increase the survival of women. The aim of this study was to discover biomarkers from liquid biopsy samples using multi-omics approach, metabolomics and proteomics for the diagnosis of ovarian cancer. To verify our biomarker candidates, we conducted comparative analysis with other previous published studies. Despite the limitations of non-invasive samples, our findings are able to discover emerging properties through the interplay between metabolites and proteins and mechanism-based biomarkers through integrated protein and metabolite analysis. The 5-year survival rate in the early and late stages of ovarian cancer differs by 63%. In addition, a liquid biopsy is necessary because there are no symptoms in the early stage and tissue collection is difficult without using invasive methods. Therefore, there is a need for biomarkers to achieve this goal. In this study, we found blood-based metabolite or protein biomarker candidates for the diagnosis of ovarian cancer in the 20 clinical samples (10 ovarian cancer patients and 10 healthy control subjects). Plasma metabolites and proteins were measured and quantified using mass spectrometry in ovarian cancer patients and control groups. We identified the differential abundant biomolecules (34 metabolites and 197 proteins) and statistically integrated molecules of different dimensions to better understand ovarian cancer signal transduction and to identify novel biological mechanisms. In addition, the biomarker reliability was verified through comparison with existing research results. Integrated analysis of metabolome and proteome identified emerging properties difficult to grasp with the single omics approach, more reliably interpreted the cancer signaling pathway, and explored new drug targets. Especially, through this analysis, proteins (PPCS, PMP2, and TUBB) and metabolites (L-carnitine and PC-O (30:0)) related to the carnitine system involved in cancer plasticity were identified. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer remains the most lethal gynecological cancer in women. There is a critical need to develop novel strategies that can be used to improve the survival of patients with advanced and recurrent ovarian cancer. Preclinical and early clinical studies with single-targeted agents have shown limited antitumor activity in ovarian cancer. In this study, we found that combined treatment of several FDA-approved targeted drugs—sunitinib, dasatinib, and everolimus—results in simultaneous inhibition of multiple signaling pathways and a better anti-tumor activity than any single treatment. This combination also significantly improves efficacy of paclitaxel in human ovarian cancer. This study may provide a potential combination therapy for the treatment of advanced ovarian cancer. More effective therapy is needed to improve the survival of patients with advanced and recurrent ovarian cancer. Preclinical and early clinical studies with single molecular targeted agents have shown limited antitumor activity in ovarian cancer, likely due to compensation by alternative growth/survival pathways. An emerging strategy in overcoming resistance is to combine inhibitors targeting multiple pathways. In this study, we used a novel strategy of combining several FDA-approved targeted drugs, including sunitinib, dasatinib, and everolimus, in human ovarian cancers. Combination of the tyrosine kinase inhibitor sunitinib with the SRC inhibitor dasatinib showed synergistic anti-tumor activity in human ovarian cancer cells. The increased activity was associated with inhibition of the STAT3, SRC, and MAPK signaling pathways, but not AKT signaling. To inhibit the PI3K/AKT/mTOR pathway, we added the mTOR inhibitor everolimus, which further increased anti-tumor activity in cells. Combined treatment with sunitinib, dasatinib, and everolimus also resulted in greater inhibition of human ovarian tumor growth in mice. Furthermore, the triple combination also synergistically increased the anti-tumor activity of paclitaxel, both in vitro and in vivo. Taken together, our results demonstrate that simultaneous inhibition of several signaling pathways results in better anti-tumor activity compared to inhibiting any of these signaling pathways alone. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumour cells have been shown to demonstrate changes in metabolic pathways as compared to normal cells. Colorectal cancer (CRC) is one of the most frequently diagnosed cancers globally. Some studies suggest that microRNAs (miRNAs) could play potential role in cancer cell metabolism. Our review aims to identify the role of different miRNAs in regulating the metabolism of CRC cells. Certain miRNAs could become potential biomarkers and even therapeutic targets based on their importance in CRC cell metabolism. Colorectal cancer (CRC) is one of the most frequently diagnosed cancers, with a high mortality rate globally. The pathophysiology of CRC is mainly initiated by alteration in gene expression, leading to dysregulation in multiple signalling pathways and cellular processes. Metabolic reprogramming is one of the important cancer hallmarks in CRC, which involves the adaptive changes in tumour cell metabolism to sustain the high energy requirements for rapid cell proliferation. There are several mechanisms in the metabolic reprogramming of cancer cells, such as aerobic glycolysis, oxidative phosphorylation, lactate and fatty acids metabolism. MicroRNAs (miRNAs) are a class of non-coding RNAs that are responsible for post-transcriptional regulation of gene expression. Differential expression of miRNAs has been shown to play an important role in different aspects of tumorigenesis, such as proliferation, apoptosis, and drug resistance, as well as metabolic reprogramming. Increasing evidence also reports that miRNAs could function as potential regulators of metabolic reprogramming in CRC cells. This review provides an insight into the role of different miRNAs in regulating the metabolism of CRC cells as well as to discuss the potential role of miRNAs as biomarkers or therapeutic targets in CRC tumour metabolism. [ABSTRACT FROM AUTHOR]

Simple Summary: Epstein-Barr virus (EBV) infection is known to contribute in nasopharyngeal carcinoma (NPC) carcinogenesis. The oncogenic roles of the EBV proteins and non-coding RNAs in NPC are becoming evident with the aid of current advances in genome-wide and in-depth molecular analyses. This current work provides a comprehensive overview, which covers recent understandings of the pathogenic role of EBV infection in NPC. Perspectives on molecular mechanisms, which are involved in the pathogenesis of NPC, focusing on the connection between EBV and NPC cells and the corresponding signaling pathways are highlighted. Cancer hallmarks associated with EBV in NPC development are also discussed herein. Nasopharyngeal carcinoma (NPC) is one of the most common tumors occurring in China and Southeast Asia. Etiology of NPC seems to be complex and involves many determinants, one of which is Epstein-Barr virus (EBV) infection. Although evidence demonstrates that EBV infection plays a key role in NPC carcinogenesis, the exact relationship between EBV and dysregulation of signaling pathways in NPC needs to be clarified. This review focuses on the interplay between EBV and NPC cells and the corresponding signaling pathways, which are modulated by EBV oncoproteins and non-coding RNAs. These altered signaling pathways could be critical for the initiation and progression of NPC. [ABSTRACT FROM AUTHOR]

The identification of specific epidermal growth factor receptor (EGFR)-activating mutations heralded a breakthrough in non-small-cell lung cancer (NSCLC) treatments, with the subsequent development of EGFR-tyrosine kinase inhibitor (TKIs) becoming the first-line therapy for patients harboring EGFR mutations. However, acquired resistance to EGFR-TKIs inevitably occurs in patients following initial TKI treatment, leading to disease progression. Various mechanisms are behind the acquired resistance, and mainly include (1) target gene modification, (2) alternative parallel pathway activation, (3) downstream pathway activation, and (4) histological/phenotypic transformation. Approaches to combat the acquired resistance have been investigated according to these mechanisms. Newer generations of TKIs have been developed to target the secondary/tertiary EGFR mutations in patients with acquired resistance. In addition, combination therapies have been developed as another promising strategy to overcome acquired resistance through the activation of other signaling pathways. Thus, in this review, we summarize the mechanisms for acquired resistance and focus on the potential corresponding therapeutic strategies for acquired resistance. [ABSTRACT FROM AUTHOR]

Metastasis represents a serious complication in the treatment of cancer. Flavonoids are plant secondary metabolites exerting various health beneficiary effects. The effects of flavonoids against cancer are associated not only with early stages of the cancer process, but also with cancer progression and spread into distant sites. Flavonoids showed potent anti-cancer effects against various cancer models in vitro and in vivo, mediated via regulation of key signaling pathways involved in the migration and invasion of cancer cells and metastatic progression, including key regulators of epithelial-mesenchymal transition or regulatory molecules such as MMPs, uPA/uPAR, TGF-β and other contributors of the complex process of metastatic spread. Moreover, flavonoids modulated also the expression of genes associated with the progression of cancer and improved inflammatory status, a part of the complex process involved in the development of metastasis. Flavonoids also documented clear potential to improve the anti-cancer effectiveness of conventional chemotherapeutic agents. Most importantly, flavonoids represent environmentally-friendly and cost-effective substances; moreover, a wide spectrum of different flavonoids demonstrated safety and minimal side effects during long-termed administration. In addition, the bioavailability of flavonoids can be improved by their conjugation with metal ions or structural modifications by radiation. In conclusion, anti-cancer effects of flavonoids, targeting all phases of carcinogenesis including metastatic progression, should be implemented into clinical cancer research in order to strengthen their potential use in the future targeted prevention and therapy of cancer in high-risk individuals or patients with aggressive cancer disease with metastatic potential. [ABSTRACT FROM AUTHOR]

The small GTPase Rac1 has been implicated in a variety of dynamic cell biological processes, including cell proliferation, cell survival, cell-cell contacts, epithelial mesenchymal transition (EMT), cell motility, and invasiveness. These processes are orchestrated through the fine tuning of Rac1 activity by upstream cell surface receptors and effectors that regulate the cycling Rac1-GDP (off state)/Rac1-GTP (on state), but also through the tuning of Rac1 accumulation, activity, and subcellular localization by post translational modifications or recruitment into molecular scaffolds. Another level of regulation involves Rac1 transcripts stability and splicing. Downstream, Rac1 initiates a series of signaling networks, including regulatory complex of actin cytoskeleton remodeling, activation of protein kinases (PAKs, MAPKs) and transcription factors (NFkB, Wnt/β-catenin/TCF, STAT3, Snail), production of reactive oxygen species (NADPH oxidase holoenzymes, mitochondrial ROS). Thus, this GTPase, its regulators, and effector systems might be involved at different steps of the neoplastic progression from dysplasia to the metastatic cascade. After briefly placing Rac1 and its effector systems in the more general context of intestinal homeostasis and in wound healing after intestinal injury, the present review mainly focuses on the several levels of Rac1 signaling pathway dysregulation in colorectal carcinogenesis, their biological significance, and their clinical impact. [ABSTRACT FROM AUTHOR]

Cancer is characterised by uncontrolled cell division and abnormal cell growth, which is largely caused by a variety of gene mutations. There are continuous efforts being made to develop effective cancer treatments as resistance to current anticancer drugs has been on the rise. Natural products represent a promising source in the search for anticancer treatments as they possess unique chemical structures and combinations of compounds that may be effective against cancer with a minimal toxicity profile or few side effects compared to standard anticancer therapy. Extensive research on natural products has shown that bioactive natural compounds target multiple cellular processes and pathways involved in cancer progression. In this review, we discuss honokiol, a plant bioactive compound that originates mainly from the Magnolia species. Various studies have proven that honokiol exerts broad-range anticancer activity in vitro and in vivo by regulating numerous signalling pathways. These include induction of G0/G1 and G2/M cell cycle arrest (via the regulation of cyclin-dependent kinase (CDK) and cyclin proteins), epithelial–mesenchymal transition inhibition via the downregulation of mesenchymal markers and upregulation of epithelial markers. Additionally, honokiol possesses the capability to supress cell migration and invasion via the downregulation of several matrix-metalloproteinases (activation of 5′ AMP-activated protein kinase (AMPK) and KISS1/KISS1R signalling), inhibiting cell migration, invasion, and metastasis, as well as inducing anti-angiogenesis activity (via the down-regulation of vascular endothelial growth factor (VEGFR) and vascular endothelial growth factor (VEGF)). Combining these studies provides significant insights for the potential of honokiol to be a promising candidate natural compound for chemoprevention and treatment. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite advances in surgical and chemotherapeutic options, most patients with advanced EOC have a relapse within three years of diagnosis. Unfortunately, recurrent disease is generally not curable. Recent advances in maintenance therapy with anti-angiogenic agents or Poly ADP-ribose polymerase (PARP) inhibitors provided a substantial benefit concerning progression-free survival among certain women with advanced EOC. However, effective treatment options remain limited in most recurrent cases. Therefore, validated novel molecular therapeutic targets remain urgently needed in the management of EOC. Signal transducer and activator of transcription-3 (STAT3) and STAT5 are aberrantly activated through tyrosine phosphorylation in a wide variety of cancer types, including EOC. Extrinsic tumor microenvironmental factors in EOC, such as inflammatory cytokines, growth factors, hormones, and oxidative stress, can activate STAT3 and STAT5 through different mechanisms. Persistently activated STAT3 and, to some extent, STAT5 increase EOC tumor cell proliferation, survival, self-renewal, angiogenesis, metastasis, and chemoresistance while suppressing anti-tumor immunity. By doing so, the STAT3 and STAT5 activation in EOC controls properties of both tumor cells and their microenvironment, driving multiple distinct functions during EOC progression. Clinically, increasing evidence indicates that the activation of the STAT3/STAT5 pathway has significant correlation with reduced survival of recurrent EOC, suggesting the importance of STAT3/STAT5 as potential therapeutic targets for cancer therapy. This review summarizes the distinct role of STAT3 and STAT5 activities in the progression of EOC and discusses the emerging therapies specifically targeting STAT3 and STAT5 signaling in this disease setting. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting the proliferation and survival of tumor cells. As a ubiquitously-expressed transcription factor, STAT3 has commonly been considered an "undruggable" target for therapy; thus, much research has focused on targeting upstream pathways to reduce the expression or phosphorylation/activation of STAT3 in tumor cells. Recently, however, novel approaches have been developed to directly inhibit STAT3 in human cancers, in the hope of reducing the survival and proliferation of tumor cells. Several of these agents are nucleic acid-based, including the antisense molecule AZD9150, CpG-coupled STAT3 siRNA, G-quartet oligodeoxynucleotides (GQ-ODNs), and STAT3 decoys. While the AZD9150 and CpG-STAT3 siRNA interfere with STAT3 expression, STAT3 decoys and GQ-ODNs target constitutively activated STAT3 and modulate its ability to bind to target genes. Both STAT3 decoy and AZD9150 have advanced to clinical testing in humans. Here we will review the current understanding of the structures, mechanisms, and potential clinical utilities of the nucleic acid-based STAT3 inhibitors. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is one of the most prominent diseases in the world, and the treatments for BC have many limitations, such as resistance and a lack of reliable biomarkers. Currently the Hippo pathway is emerging as a tumor suppressor pathway with its four core components that regulate downstream transcriptional targets. In this review, we introduce the present targeted therapies of BC, and then discuss the roles of the Hippo pathway in BC. Finally, we summarize the evidence of the small molecule inhibitors that target the Hippo pathway, and then discuss the possibilities and future direction of the Hippo-targeted drugs for BC therapy. [ABSTRACT FROM AUTHOR]

Drug repurposing is a fast and consolidated approach for the research of new active compounds bypassing the long streamline of the drug discovery process. Several drugs in clinical practice have been reported for modulating the major Hippo pathway's terminal effectors, namely YAP (Yes1-associated protein), TAZ (transcriptional co-activator with PDZ-binding motif) and TEAD (transcriptional enhanced associate domains), which are directly involved in the regulation of cell growth and tissue homeostasis. Since this pathway is known to have many cross-talking phenomena with cell signaling pathways, many efforts have been made to understand its importance in oncology. Moreover, this could be relevant to obtain new molecular tools and potential therapeutic assets. In this review, we discuss the main mechanisms of action of the best-known compounds, clinically approved or investigational drugs, able to cross-talk and modulate the Hippo pathway, as an attractive strategy for the discovery of new potential lead compounds. [ABSTRACT FROM AUTHOR]

Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma (MM) constitutes a very aggressive tumor that arises from the pleural or peritoneal cavities and is highly refractory to conventional therapies. Several key genetic alterations are associated with the development and progression of MM including mutations of the CDKN2A/ARF, NF2, and BAP1 tumor-suppressor genes. Notably, activating oncogene mutations are very rare; thus, it is difficult to develop effective inhibitors to treat MM. The NF2 gene encodes merlin, a protein that regulates multiple cell-signaling cascades including the Hippo pathway. MMs also exhibit inactivation of Hippo pathway components including LATS1/2, strongly suggesting that merlin-Hippo pathway dysregulation plays a key role in the development and progression of MM. Furthermore, Hippo pathway inactivation has been shown to result in constitutive activation of the YAP1/TAZ transcriptional coactivators, thereby conferring malignant phenotypes to mesothelial cells. Critical YAP1/TAZ target genes, including prooncogenic CCDN1 and CTGF, have also been shown to enhance the malignant phenotypes of MM cells. Together, these data indicate the Hippo pathway as a therapeutic target for the treatment of MM, and support the development of new strategies to effectively target the activation status of YAP1/TAZ as a promising therapeutic modality for this formidable disease. [ABSTRACT FROM AUTHOR]