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MicroRNAs (miRNAs) are small non-coding RNAs that play key roles in tumorigenesis as modulators of cell signaling pathways. miRNA expression has been found to be dysregulated in several human and canine tumors, but data are not yet available on canine meningioma. In this study, we analyzed the expression of 12 miRNAs (i.e. miR-335, miR-200a, miR-98, miR-96, miR-190a, miR-29c, miR-219-5p, miR-155, miR-146a, miR-145, miR-136, miR-451) by RT-qPCR in a series of 41 formalin-fixed, paraffin-embedded canine meningiomas, and normal arachnoid samples. We identified 8 dysregulated miRNAs that might be involved in canine meningioma pathogenesis. Five miRNAs (i.e. miR-96, miR-145, miR-335, miR-200a, miR-29c), were downregulated in tumor samples and 3 (i.e. miR-136, miR-155, miR-146a) were upregulated. Moreover, miR-200a was overexpressed in grade III compared to grade I and grade II meningiomas, suggesting that it might have a dual role in tumor initiation and progression. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses suggest that dysregulated miRNAs might influence cellular processes and pathways mainly involved in tumor cell migration, extracellular matrix interactions, cell proliferation, and inflammatory responses. The characterization of miRNA functions in canine meningiomas is needed to assess their potential clinical utility, also in view of the relevance of the dog as a potential spontaneous animal model of human disease.

1,3-Dichloro-2-propanol (1,3-DCP), a food contaminant, exerts carcinogenic effects in multiple organs, including the liver and kidneys, in rats. However, the underlying mechanisms of 1,3-DCP-induced carcinogenesis remain unclear. Here, the in vivo mutagenicity and tumor-promoting activity of 1,3-DCP in the liver and kidneys were evaluated using medium-term gpt delta rat models previously established in our laboratory (GPG and GNP models). Six-week-old male F344 gpt delta rats were treated with 0 or 50 mg/kg body weight/day 1,3-DCP by gavage for 4 weeks. After 2 weeks of cessation, partial hepatectomy or unilateral nephrectomy was performed to collect samples for in vivo mutation assays, followed by single administration of diethylnitrosamine (DEN) for tumor initiation. One week after DEN injection, 1,3-DCP treatment was resumed, and tumor-promoting activity was evaluated in the residual liver or kidneys by histopathological analysis of preneoplastic lesions. gpt mutant frequencies increased in excised liver and kidney tissues following 1,3-DCP treatment. 1,3-DCP did not affect the development of glutathione S-transferase placental form-positive foci in residual liver tissues, but enhanced atypical tubule hyperplasia in residual kidney tissues. Detailed histopathological analyses revealed glomerular injury and increased cell proliferation of renal tubular cells in residual kidney tissues of rats treated with 1,3-DCP. These results suggested possible involvement of genotoxic mechanisms in 1,3-DCP-induced carcinogenesis in the liver and kidneys. In addition, we found that 1,3-DCP exhibited limited tumor-promoting activity in the liver, but enhanced clonal expansion in renal carcinogenesis via proliferation of renal tubular cells following glomerular injury.

PDLIM1, a member of the PDZ-LIM family, is a cytoskeletal protein and functions as a platform to form distinct protein complexes, thus participating in multiple physiological processes such as cytoskeleton regulation and synapse formation. Emerging evidence demonstrates that PDLIM1 is dysregualted in a variety of tumors and plays essential roles in tumor initiation and progression. In this review, we summarize the structure and function of PDLIM1, as well as its important roles in human cancers.

Non-small cell lung cancer (NSCLC) is a highly aggressive cancer with one of the most prevalent malignant tumors. Metastasis in NSCLC is the major cause of treatment failure and cancer-related deaths. Yes-associated protein (YAP) is a transcriptional coactivator regulated by the evolutionarily conserved Hippo signaling pathway that regulates organ size, growth, and regeneration. YAP is highly expressed in several malignant tumor types. Furthermore, YAP promotes tumor initiation and/or progression in various types of cancer. However, it is unclear whether YAP contributes to the metastasis in NSCLC and serves as a useful therapeutic target. Here, we investigated whether levels of YAP correlate with metastatic phenotype in NSCLC cells and serve as a useful therapeutic target. We found that high levels of YAP associate with high cell migration, invasion, and metastasis in NSCLC cell lines. Furthermore, YAP siRNA decreased the migration and invasion in NSCLC cells. Additionally, verteporfin, an agent used for the treatment of symptomatic polypoidal choroidal vasculopathy, decreased the expression of YAP and inhibited migration, invasion, and metastasis in NSCLC cells. Thus, the study suggests that targeting YAP may present a new avenue to develop therapeutics against metastasis in NSCLC and that verteporfin has potential molecular therapeutic strategy for the treatment of metastatic NSCLC.

Lipofilling may constitute a technique to assist reconstruction of breasts following prophylactic mastectomy for patients with mutated BRCA1 or BRCA2 genes. However, to date it is not clear whether adipose-derived stromal cells (ADSCs) increase the risk of tumor initiation and progression in this situation. Therefore, the interactions of BRCA1 mutated breast cancer cell lines with normal ADSCs were investigated in the present study. Characteristics of MDA-MB-436 (BRCA1 c.5277 + 1G > A) and HCC1937 (BRCA1 p.Gln1756.Profs*74) were compared to MDA-MB-231 and T47D BRCA1/2 wild-type breast cancer cell lines. ADSCs were cultivated from lipoaspirates of a panel of BRCA1/2- wildtype patients. Interactions of conditioned medium (CM) of these cells with the breast cancer lines were studied using proliferation and migration assays as well as adipokine expression western blot arrays. CM of ADSCs exhibit a dose-dependent stimulation of the proliferation of the breast cancer cell lines. However, of the ADSC preparations tested, only 1 out of 18 samples showed a significant higher stimulation of BRCA1-mutated MDA-MB-436 versus wildtype MDA-MB-231 cells, and all CM revealed lower stimulatory activity for BRCA1-mutated HCC1937 versus wildtype T47D cells. Additionally, migration of breast cancer cells in response to CM of ADSCs proved to be equivalent or slower for BRCA1/2 mutated versus nonmutated cancer cells and, with exception of angiopoietin-like 2, induced expression of adipokines showed no major difference. Effects of media conditioned by normal ADSCs showed largely comparable effects on BRCA1-mutated and wildtype breast cancer cell lines thus advocating lipofilling, preferentially employing allogeneic non-mutated ADSCs.

Colorectal cancer (CRC) is one of the most common cancer types globally with a 5‐year survival rate of, We identified two differentially methylated regions (DMRs) between colorectal cancer samples and normal controls using a sliding window method. Receiver operating characteristic (ROC) analysis suggests these two DMRs have potential for distinguishing cancers from normal controls using both the TCGA dataset and our validation set.

MicroRNAs (miRNAs), a recently discovered class of noncoding RNAs, play pivotal roles in regulating fundamental biological processes by suppressing the expression of target genes. Aberrant miRNA expression is commonly correlated with human diseases, including cancers. Anti-miRNA oligonucleotides provide an innovative therapeutic strategy for silencing disease-associated miRNAs. However, the clinical application of anti-miRNA therapy has been limited by formulation challenges and physiological delivery barriers. Here, to provide the safe and effective tumor-targeted delivery of anti-miRNAs, we designed carrier-free maleimide-functionalized anti-miRNAs (MI-Anti-miRNAs) that enable "piggybacking" onto albumin in vivo. These functionalized MI-Anti-miRNAs covalently bind to cysteine-34 of endogenous albumin within minutes. In addition to resulting in a markedly extended blood circulation lifetime, this strategy allows MI-Anti-miRNAs to "hitchhike" to the tumor site. Importantly, in situ-generated albumin-Anti-miRNAs are capable of intracellularly internalizing highly negatively charged anti-miRNA molecules and knocking down target miRNAs. In particular, MI-Anti-miRNAs that targeted miRNA-21, which is involved in tumor initiation, progression, invasion, and metastasis in several types of cancer, successfully repressed miRNA-21 activity, resulting in a superior antitumor activity in both solid and metastatic tumor models without causing systemic toxicity. This endogenous albumin-piggybacking approach using MI-Anti-miRNAs provides a simple and broadly applicable platform strategy for the systemic delivery of anti-miRNA therapeutics.

Cancer stem cells (CSCs) are a small population of heterogeneous tumor cells with the capacity of self-renewal and aberrant differentiation for immortality and divergent lineages of cancer cells. In contrast to bulky tumor cells, CSCs remain less differentiated and resistant to therapy even when targeted with tissue-specific antigenic markers. This makes CSCs responsible for not only tumor initiation, development, but also tumor recurrence. Emerging evidence suggests that CSCs can undergo cell senescence, a non-proliferative state of cells in response to stress. While cell senescence attenuates tumor cell proliferation, it is commonly regarded as a tumor suppressive mechanism. However, mounting research indicates that CSC senescence also provides these cells with the capacity to evade cytotoxic effects from cancer therapy, exacerbating cancer relapse and metastasis. Recent studies demonstrate that senescence drives reprogramming of cancer cell towards stemness and promotes CSC generation. In this review, we highlight the origin, heterogeneity and senescence regulatory mechanisms of CSCs, the complex relationship between CSC senescence and tumor therapy, and the recent beneficial effects of senotherapy on eliminating senescent tumor cells.

Despite a high clinical need for the treatment of colorectal carcinoma (CRC) as the second leading cause of cancer-related deaths, targeted therapies are still limited. The multifunctional enzyme Transglutaminase 2 (TGM2), which harbors transamidation and GTPase activity, has been implicated in the development and progression of different types of human cancers. However, the mechanism and role of TGM2 in colorectal cancer are poorly understood. Here, we present TGM2 as a promising drug target.In primary patient material of CRC patients, we detected an increased expression and enzymatic activity of TGM2 in colon cancer tissue in comparison to matched normal colon mucosa cells. The genetic ablation of TGM2 in CRC cell lines using shRNAs or CRISPR/Cas9 inhibited cell expansion and tumorsphere formation. In vivo, tumor initiation and growth were reduced upon genetic knockdown of TGM2 in xenotransplantations. TGM2 ablation led to the induction of Caspase-3-driven apoptosis in CRC cells. Functional rescue experiments with TGM2 variants revealed that the transamidation activity is critical for the pro-survival function of TGM2. Transcriptomic and protein–protein interaction analyses applying various methods including super-resolution and time-lapse microscopy showed that TGM2 directly binds to the tumor suppressor p53, leading to its inactivation and escape of apoptosis induction.We demonstrate here that TGM2 is an essential survival factor in CRC, highlighting the therapeutic potential of TGM2 inhibitors in CRC patients with high TGM2 expression. The inactivation of p53 by TGM2 binding indicates a general anti-apoptotic function, which may be relevant in cancers beyond CRC.

OBJECTIVE Glioma stem cells (GSCs) are responsible for tumor initiation, therapeutic resistance, and recurrence. CD146 is mainly expressed in dividing GSCs and regulates cell cycle progression. However, the evaluation of the efficacy of targeted therapy against CD146 in vivo remains to be investigated. In this study, the authors aimed to develop gene therapy targeting GSCs using chitosan oligosaccharide lactate (COL) nanoparticles (NPs) conjugated with folic acid–polyethylene glycol (FA-PEG-COL NPs) for in vitro and in vivo delivery of CD146 small-interfering RNA (siCD146) and to determine the effect of CD146 knockdown on tumor growth. METHODS To examine the uptake of NPs by tumor cells, immunofluorescence staining, flow cytometry, and in vivo imaging were performed. The knockdown effect of siCD146 was measured by western blot and water-soluble tetrazolium salt–8 assay in mouse glioma cells. The efficacy of siRNA therapy–targeted GSCs was evaluated by monitoring tumor growth through in vivo imaging and histological analysis. RESULTS In vivo accumulation of the FA-PEG-COL NPs in subcutaneous and intracranial gliomas following NP administration via a mouse tail vein was observed. Additionally, in vitro delivery of siCD146 ionically cross-linked NPs, reduced CD146 levels, and suppressed growth in the glioma tumor sphere. Evaluation of the in vivo therapeutic effects of siCD146–cross-linked NPs in a mouse glioma model revealed significant suppression of intracranial tumor growth, with complete removal of the tumor observed in some mice on histological examination. Furthermore, delivery of siCD146 significantly reduced the Ki-67 index in residual tumor tissues relative to that in control mice. CONCLUSIONS CD146 is a potential therapeutic target, and folic acid–conjugated NPs delivering siRNA may facilitate gene therapy in malignant gliomas.

Tumor immunity represents a new avenue for cancer therapy. Immune checkpoint inhibitors have successfully improved outcomes in several tumor types. In addition, currently, immune cell-based therapy is also attracting significant attention. However, the clinical efficacy of these treatments requires further improvement. The mechanisms through which cancer cells escape the immune response must be identified and clarified. Cancer stem cells (CSCs) play a central role in multiple aspects of malignant tumors. CSCs can initiate tumors in partially immunocompromised mice, whereas non-CSCs fail to form tumors, suggesting that tumor initiation is a definitive function of CSCs. However, the fact that non-CSCs also initiate tumors in more highly immunocompromised mice suggests that the immune evasion property may be a more fundamental feature of CSCs rather than a tumor-initiating property. In this review, we summarize studies that have elucidated how CSCs evade tumor immunity and create an immunosuppressive milieu with a focus on CSC-specific characteristics and functions. These profound mechanisms provide important clues for the development of novel tumor immunotherapies., Highlights • Cancer stem cells (CSCs) play a central role in multiple aspects of malignant tumors. • Immune evasion is a fundamental feature of CSCs. • Immune evasion mechanisms must be precisely clarified to improve tumor immunotherapy. • CSCs are promising targets for tumor immunotherapy.

Long noncoding RNAs (lncRNAs) are involved in multiple functions such as the regulation of cellular homeostasis. They play prominent roles in the pathogenesis of human cancer, and contribute to every hallmark of cancer. The novel cancer-related lncRNA DLX6 antisense RNA 1 (DLX6-AS1) plays an essential regulatory role in enhancing and initiating carcinogenesis and tumor progression. This progression is due to the aberrant regulation of downstream factors in vitro as well as in vivo. DLX6-AS1 is significantly dysregulated in various cancers. DLX6-AS1 functions in tumor initiation and progression are regulated at the epigenetic, transcription, and posttranscriptional regulation levels. DLX6-AS1 functions as an oncogene, binding to miRNA targeting sites competing endogenous RNAs and causing the upregulation of downstream tumor-related genes and carcinogenesis. The regulation and detailed molecular mechanisms of DLX6-AS1 and its potential role in malignancies are comprehensively described in this paper. DLX6-AS1 has the potential to become a novel biomarker and therapeutic target for cancer.

Emerging evidence has shown that several SOX family transcription factors are key regulators of stem/progenitor cell fates in the mammary gland. These cell-fate regulators are often upregulated in breast cancer and contribute to tumor initiation and progression. They induce lineage plasticity and the epithelial-mesenchymal transition, which promotes tumor invasion, metastasis, and therapeutic resistance. SOX factors act through modulating multiple oncogenic signaling pathways in breast cancer. In addition to the cell-autonomous functions, new evidence suggests they can shape the tumor immune microenvironment. Here, we will review the molecular and functional evidence linking SOX factors with mammary gland development and discuss how these cell-fate regulators are co-opted in breast cancer.

Metastasis is the primary cause of cancer mortality and an improved understanding of its pathology is critical to the development of novel therapeutic approaches. Mechanism-based therapeutic strategies require insight into the timing of tumor cell dissemination, seeding of distant organs, formation of occult lesions and critically, their release from dormancy. Due to imaging limitations, primary tumors can only be detected when they reach a relatively large size (e.g. >1 cm(3)), which, based on our understanding of tumor evolution, occurs approximately 10 years and about 30 doubling times following tumor initiation. Genomic profiling of paired primary tumors and metastases has suggested that tumor seeding at secondary sites occurs early during tumor progression and frequently, years prior to clinical diagnosis. Following seeding, tumor cells may enter into and remain in a dormant state, and if they survive and are released from dormancy, they can proliferate into an overt lesion. The timeline of tumor initiation and metastatic dormancy is regulated by tumor interactions with its microenvironment, angiogenesis and tumor-specific cytotoxic T-lymphocyte (CTL) responses. Therefore, a better understanding of the cellular interactions responsible for immune evasion and/or tumor cell release from dormancy would facilitate the development of therapeutics targeted against this critical part of tumor progression. The immunosuppressive mechanisms mediated by myeloid-derived suppressor cells (MDSCs) contribute to tumor progression and, we posit, promote tumor cell escape from CTL-associated dormancy. Thus, while clinical and translational research has demonstrated a role for MDSCs in facilitating tumor progression and metastasis through tumor escape from adoptive and innate immune responses (T-, natural killer (NK) and B-cell responses), few studies have considered the role of MDSCs in tumor release from dormancy. In this review, we discuss MDSC expansion, driven by tumor burden associated growth factor secretion and their role in tumor cell escape from dormancy, resulting in manifest metastases. Thus, the therapeutic strategies to inhibit MDSC expansion and function may provide an approach to delay metastatic relapse and prolong the survival of patients with advanced malignancies.

Autophagy is primarily a homeostatic and catabolic process that is increasingly being recognized to have a pivotal role in the initiation and maintenance of cancer cells, as well as in the emergence of therapeutic resistance. Moreover, in the tumor microenvironment (TME) autophagy plays a crucial and sometimes dichotomous role in tumor progression. Recent studies show that during the early stages of tumor initiation, autophagy suppresses tumorigenesis. However, in the advanced stage of tumorigenesis, autophagy promotes cancer progression by protecting cancer cells against stressful conditions and therapeutic assault. Specifically, in cancer-associated fibroblasts (CAFs), autophagy promotes tumorigenesis not only by providing nutrients to the cancerous cells but also by inducing epithelial to mesenchymal transition, angiogenesis, stemness, and metastatic dissemination of the cancer cells, whereas in the immune cells, autophagy induces the tumor-localized immune response. In the TME, CAFs play a crucial role in cancer cell metabolism, immunoreaction, and growth. Therefore, targeting autophagy in CAFs by several pharmacological inducers like rapamycin or the inhibitor such as chloroquine has gained importance in preclinical and clinical trials. In the present review, we summarized the basic mechanism of autophagy in CAFs along with its role in driving tumorigenic progression through several emerging as well as classical hallmarks of cancer. We also addressed various autophagy inducers as well as inhibitors of autophagy for more efficient cancer management. Eventually, we prioritized some of the outstanding issues that must be addressed with utmost priority in the future to elucidate the role of autophagy in CAFs on tumor progression and therapeutic intervention.

Increasing proofs have declared that liver cancer stem cells (CSCs) are the main contributors to tumor initiation, metastasis, therapy resistance, and recurrence of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying CSCs regulation remain largely unclear. Recently, PCNA-associated factor (PAF) was identified to play a key role in maintaining breast cancer cell stemness, but its role in liver cancer stem cells has not been declared yet. Herein, we found that both mRNA and protein expression levels of PAF were significantly higher in HCC tissues and cell lines than normal controls. CSC-enriched hepatoma spheres displayed an increase in PAF expression compared to monolayer-cultured cells. Both loss-of-function and gain-of-function experiments revealed that PAF enhanced sphere formation and the percentage of CD133(+) or EpCAM(+) cells in HCCLM3 and Huh7 cells. In the xenograft HCC tumor model, tumor initiation rates and tumor growth were suppressed by knockdown of PAF. Mechanistically, PAF can amplify the self-renewal of liver CSCs by activating β-catenin signaling. Taken together, our results demonstrate that PAF plays a crucial role in maintaining the hepatoma cell stemness by β-catenin signaling. Abbreviations: CSCs: cancer stem cells; HCC: hepatocellular carcinoma; PAF: pCNA-associated factor.

The microbiota influences human health and the development of diverse diseases, including cancer. Microbes can influence tumor initiation and development in either a positive or negative manner. In addition, the composition of the gut microbiota affects the efficacy and toxicity of cancer therapeutics as well as therapeutic resistance. The striking impact of microbiota on oncogenesis and cancer therapy provides compelling evidence to support the notion that manipulating microbial networks represents a promising strategy for treating and preventing cancer. Specific microbes or the microbial ecosystem can be modified via a multiplicity of processes, and therapeutic methods and approaches have been evolving. Microbial manipulation can be applied as an adjunct to traditional cancer therapies such as chemotherapy and immunotherapy. Furthermore, this approach displays great promise as a stand-alone therapy following the failure of standard therapy. Moreover, such strategies may also benefit patients by avoiding the emergence of toxic side effects that result in treatment discontinuation. A better understanding of the host-microbial ecosystem in patients with cancer, together with the development of methodologies for manipulating the microbiome, will help expand the frontiers of precision cancer therapeutics, thereby improving patient care. This review discusses the roles of the microbiota in oncogenesis and cancer therapy, with a focus on efforts to harness the microbiota to fight cancer.

Cancer stem cells (CSCs) are subpopulations of tumor cells that possess abilities for self-renewal, differentiation, and tumor initiation. These rare but therapy-recalcitrant cells are assumed to repopulate tumors following administration of systemic chemotherapy driving therapy failure, tumor recurrence, and disease progression. In early clinical trials, anti-CSC therapies have found limited success to-date possibly due to the inherent heterogeneity and plasticity of CSCs and the incomplete characterization of essential CSC targets. Here, we review the role of 3-phosphoinositide dependent protein kinase-1 (PDPK1) as an emerging CSC target. While most previous studies have relied on CSC models which are based on lineage and tissue-specific marker profiles to define the relationships between putative target and CSC traits, this review discusses PDPK1 and its role in CSC biology with an emphasis on CSC systems which are based on proposed function like label-retaining cancer cells (LRCCs).

Exosomes are major contributors in cell to cell communication due to their ability to transfer biological material such as protein, RNA, DNA, and miRNA. Additionally, they play a role in tumor initiation, promotion, and progression, and recently, they have emerged as a potential source of information on tumor detection and may be useful as diagnostic, prognostic, and predictive tools. This review focuses on exosomes from lung cancer with a focus on EGFR mutations. Here, we outline the role of exosomes and their functional effect in carcinogenesis, tumor progression, and metastasis. Finally, we discuss the possibility of exosomes as novel biomarkers in early detection, diagnosis, assessment of prognosis, and prediction of therapeutic response in EGFR-mutated lung cancer.

Background BIR repeat-containing ubiquitin conjugating enzyme (BRUCE) is a liver tumor suppressor, which is downregulated in a large number of patients with liver diseases. BRUCE facilitates DNA damage repair to protect the mouse liver against the hepatocarcinogen diethylnitrosamine (DEN)-dependent acute liver injury and carcinogenesis. While there exists an established pathologic connection between fibrosis and hepatocellular carcinoma (HCC), DEN exposure alone does not induce robust hepatic fibrosis. Further studies are warranted to identify new suppressive mechanisms contributing to DEN-induced fibrosis and HCC. Aim To investigate the suppressive mechanisms of BRUCE in hepatic fibrosis and HCC development. Methods Male C57/BL6/J control mice [loxp/Loxp; albumin-cre (Alb-cre)-] and BRUCE Alb-Cre KO mice (loxp/Loxp; Alb-Cre+) were injected with a single dose of DEN at postnatal day 15 and sacrificed at different time points to examine liver disease progression. Results By using a liver-specific BRUCE knockout (LKO) mouse model, we found that BRUCE deficiency, in conjunction with DEN exposure, induced hepatic fibrosis in both premalignant as well as malignant stages, thus recapitulating the chronic fibrosis background often observed in HCC patients. Activated in fibrosis and HCC, β-catenin activity depends on its stabilization and subsequent translocation to the nucleus. Interestingly, we observed that livers from BRUCE KO mice demonstrated an increased nuclear accumulation and elevated activity of β-catenin in the three stages of carcinogenesis: Pre-malignancy, tumor initiation, and HCC. This suggests that BRUCE negatively regulates β-catenin activity during liver disease progression. β-catenin can be activated by phosphorylation by protein kinases, such as protein kinase A (PKA), which phosphorylates it at Ser-675 (pSer-675-β-catenin). Mechanistically, BRUCE and PKA were colocalized in the cytoplasm of hepatocytes where PKA activity is maintained at the basal level. However, in BRUCE deficient mouse livers or a human liver cancer cell line, both PKA activity and pSer-675-β-catenin levels were observed to be elevated. Conclusion Our data support a "BRUCE-PKA-β-catenin" signaling axis in the mouse liver. The BRUCE interaction with PKA in hepatocytes suppresses PKA-dependent phosphorylation and activation of β-catenin. This study implicates BRUCE as a novel negative regulator of both PKA and β-catenin in chronic liver disease progression. Furthermore, BRUCE-liver specific KO mice serve as a promising model for understanding hepatic fibrosis and HCC in patients with aberrant activation of PKA and β-catenin.

Autophagy removes damaged organelles to inhibit malignant transformation during tumor initiation. Once a cancer matures, it uses the autophagic pathway as an energy source. Optineurin (OPTN) is an autophagy adaptor protein that recruits microtubule‐associated protein 1 light chain 3, an autophagosome marker, to the autophagosome. Despite studies of the relation between cancer progression and autophagy adaptor proteins, there are no reports to our knowledge of a correlation between hepatocellular carcinoma (HCC) and OPTN. We aimed here to investigate the effects of OPTN expression on HCC progression through autophagy. Immunohistochemistry was used to measure the OPTN expression in the tissues of 141 Japanese patients with HCC. The effects of OPTN expression on HCC progression and mitophagy were assessed using an OPTN knockout (KO) cell line in vitro. We used this KO cell line to establish and exploit a mouse model of HCC to determine the effects of OPTN expression on tumor progression. Immunohistochemical analysis showed that patients with elevated expression of OPTN experienced shorter overall survival (OS) and recurrence‐free survival (RFS). OPTN KO cells proliferated relatively slower versus wild‐type (WT) cells in vitro. Western blot analysis showed that mitophagy was suppressed in OPTN KO cells, and ATP synthesis and beta‐oxidation were reduced. The mouse model of HCC showed that OPTN KO cells formed smaller tumors versus WT cells less 10 weeks after implantation. Overall, the present findings suggest that OPTN is a key mediator of mitophagy that contributes to HCC progression through mitochondrial energy production., Optineurin (OPTN) is required for mitophagic activity as shown by the significant association of OPTN expression levels with mitochondrial beta‐oxidation. Moreover, elevated levels of OPTN were associated with worse prognosis of HCC. Our findings provide a foundation for determining the roles of other autophagy adaptor proteins in the pathogenesis and progression of HCC as well as in other cancers.

It is hypothesized that vitamin B12 may prevent tumor initiation during the early stage of carcinogenesis such as esophageal precancerous lesions (EPL), whereas an excessive level may promote tumor progression during the later stages of carcinogenesis. This study aimed to determine the role of vitamin B12 in EPL by detecting vitamin B12-related markers in both blood and diet. This case–control study based on 3-day duplicated diet samples was conducted in a high-risk area of Huai'an, China. A 100 EPL cases and 100 healthy controls matched by gender, age (± 2 years) and villages were included. Dietary intake of vitamin B12 and cobalt, plasma cobalt level, the serum levels of vitamin B12 and transcobalamin II (TC II) were quantitatively analyzed. Dietary vitamin B12 intake (p for trend = 0.384) and plasma cobalt level (p for trend = 0.253) were not associated with EPL risk, but high dietary cobalt intake (p for trend = 0.034), increased serum levels of vitamin B12 (p for trend = 0.036) and TC II (p for trend

Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPC) and tumors from 2 melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood–derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME). When patient tumors were implanted on aHM, mHM, and NOD/SCID/IL2rg−/− (NSG) cohorts, tumors appeared earlier and grew faster on NSG and mHM cohorts. We observed that immune cells differentiating in the aHM were relatively more capable of circulating peripherally, invading into tumors and interacting with the TME. A heterologous, human leukocyte antigen (HLA-A) matched cohort also yielded slower growing tumors than non–HLA-matched mHM, indicating that a less permissive immune environment inhibits tumor progression. When the aHM, mHM, and NSG cohorts were treated with immunotherapies mirroring what the originating patients received, tumor growth in the aHM accelerated, similar to the progression observed in the patients. This rapid growth was associated with decreased immune cell infiltration, reduced interferon gamma (IFNγ)–related gene expression, and a reduction in STAT3 phosphorylation, events that were replicated in vitro using tumor-derived cell lines. Implications: Engrafted adult HSPCs give rise to more tumor infiltrative immune cells, increased HLA matching leads to slower tumor initiation and growth, and continuing immunotherapy past progression can paradoxically lead to increased growth.

Wanguo Feng,1 Ruixi Zhu,2 Junlong Ma,3 Han Song2 1Department of Refractive Surgery, Dalian Aier Eye Hospital, Dalian, 116092, People’s Republic of China; 2Department of Ophthalmology, Heilongjiang Provincial Hospital, Harbin Institute of Technology, Harbin, 150036, People’s Republic of China; 3Department of Ophthalmology, Dalian University Affiliated Xinhua Hospital, Dalian, 116021, People’s Republic of ChinaCorrespondence: Han SongDepartment of Ophthalmology, Heilongjiang Provincial Hospital, Harbin Institute of Technology, Harbin, 150036, People’s Republic of ChinaEmail songhan00111@163.comBackground: Long noncoding RNA (lncRNA) has been reported to play important roles in tumor initiation. However, how lncRNA ELFN1-AS1 affects retinoblastoma development remains unclear. Thus, we sought to elucidate its functions in retinoblastoma progression.Methods: ELFN1-AS1 expression was measured in retinoblastoma tissues and normal tissues by qRT-PCR. CCK8, colony formation and Transwell assay were carried out to investigate the effects of ELFN1-AS1 knockdown on cell malignant behaviors. Bioinformatics analyses were performed to predict the relationship among ELFN1-AS1, miR-4270 and SBK1.Results: ELFN1-AS1 was highly expressed in retinoblastoma tissues and cell lines. ELFN1-AS1 was positively correlated with retinoblastoma progression and prognosis. ELFN1-AS1 knockdown curtailed retinoblastoma proliferation, migration and invasion. ELFN1-AS1 was the competing endogenous RNA for miR-4270 and promoted SBK1expression.Conclusion: Altogether, our findings demonstrated that ELFN1-AS1 promotes retinoblastoma progression through mediating miR-4270/SBK1 axis and might be a promising therapeutic target.Keywords: ELFN1-AS1, miR-4270, SBK1, retinoblastoma, progression

Protein synthesis is one of the most essential processes in every kingdom of life, and its dysregulation is a known driving force in cancer development. Multiple signaling pathways converge on the translation initiation machinery, and this plays a crucial role in regulating differential gene expression. In colorectal cancer, dysregulation of initiation results in translational reprogramming, which promotes the selective translation of mRNAs required for many oncogenic processes. The majority of upstream mutations found in colorectal cancer, including alterations in the WNT, MAPK, and PI3K\AKT pathways, have been demonstrated to play a significant role in translational reprogramming. Many translation initiation factors are also known to be dysregulated, resulting in translational reprogramming during tumor initiation and/or maintenance. In this review, we outline the role of translational reprogramming that occurs during colorectal cancer development and progression and highlight some of the most critical factors affecting the etiology of this disease.

Defining traits of platinum-tolerant cancer cells could expose new treatment vulnerabilities. Here, new markers associated with platinum-tolerant cells and tumors were identified using in vitro and in vivo ovarian cancer models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were enriched in ALDH+ cells, formed more spheroids, and expressed increased levels of stemness-related transcription factors compared with parental cells. Additionally, platinum-tolerant cells and tumors exhibited expression of the Wnt receptor Frizzled-7 (FZD7). Knockdown of FZD7 improved sensitivity to platinum, decreased spheroid formation, and delayed tumor initiation. The molecular signature distinguishing FZD7+ from FZD7− cells included epithelial-to-mesenchymal (EMT), stemness, and oxidative phosphorylation-enriched gene sets. Overexpression of FZD7 activated the oncogenic factor Tp63, driving upregulation of glutathione metabolism pathways, including glutathione peroxidase 4 (GPX4), which protected cells from chemotherapy-induced oxidative stress. FZD7+ platinum-tolerant ovarian cancer cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors. FZD7, Tp63, and glutathione metabolism gene sets were strongly correlated in the ovarian cancer Tumor Cancer Genome Atlas (TCGA) database and in residual human ovarian cancer specimens after chemotherapy. These results support the existence of a platinum-tolerant cell population with partial cancer stem cell features, characterized by FZD7 expression and dependent on the FZD7–β-catenin–Tp63–GPX4 pathway for survival. The findings reveal a novel therapeutic vulnerability of platinum-tolerant cancer cells and provide new insight into a potential “persister cancer cell” phenotype.Significance:Frizzled-7 marks platinum-tolerant cancer cells harboring stemness features and altered glutathione metabolism that depend on GPX4 for survival and are highly susceptible to ferroptosis.

BRCA1-associated protein 1 (BAP1) is emerging as an intensively studied cancer-associated gene. Germline mutations in BAP1 lead to a cancer syndrome, and somatic loss is found in several cancer types. BAP1 encodes a deubiquitinase enzyme, which plays key roles in cell-cycle regulation, cell death, and differentiation. Recent studies have demonstrated that BAP1 is also involved in several aspects of cellular metabolism, including metabolic homeostasis, glucose utilization, control of ferroptosis, and stress response. A better knowledge of the metabolic roles of cancer-associated genes is important to understanding tumor initiation and progression, as well as highlighting potential therapeutic avenues. With this review, we summarize the current knowledge regarding BAP1-mediated regulation of metabolic activities that may support new strategies to treat BAP1-mutated cancers.

The spread of primary tumor cells to distant organs, termed metastasis, is the principal cause of cancer mortality and is a critical therapeutic target in oncology. Thus, a better understanding of metastatic progression is critical for improved therapeutic approaches requiring insight into the timing of tumor cell dissemination and seeding of distant organs, which can lead to the formation of occult lesions. However, due to limitations in imaging techniques, primary tumors can only be detected when they reach a relatively large size (e.g., > 1 cm3), which, based on our understanding of tumor evolution, is 10 to 20 years (30 doubling times) following tumor initiation. Recent insights into the timing of metastasis are based on the genomic profiling of paired primary tumors and metastases, suggesting that tumor cell seeding of secondary sites occurs early during tumor progression and years prior to diagnosis. Following seeding, tumor cells may remain in a dormant state as single cells or micrometastases before emerging as overt lesions. This timeline and the role of metastatic dormancy are regulated by interactions between the tumor, its microenvironment, and tumor-specific T cell responses. An improved understanding of the mechanisms and interactions responsible for immune evasion and tumor cell release from dormancy would support the development of novel targeted therapeutics. We posit herein that the immunosuppressive mechanisms mediated by myeloid-derived suppressor cells (MDSCs) are a major contributor to tumor progression, and that these mechanisms promote tumor cell escape from dormancy. Thus, while extensive studies have demonstrated a role for MDSCs in the escape from adoptive and innate immune responses (T-, natural killer (NK)-, and B cell responses), facilitating tumor progression and metastasis, few studies have considered their role in dormancy. In this review, we discuss the role of MDSC expansion, driven by tumor burden, and its role in escape from dormancy, resulting in occult metastases, and the potential for MDSC inhibition as an approach to prolong the survival of patients with advanced malignancies.

Signaling from multiple receptor tyrosine kinases (RTK) contributes to therapeutic resistance in glioblastoma (GBM). Heparan sulfate (HS), present on cell surfaces and in the extracellular matrix, regulates cell signaling via several mechanisms. To investigate the role for HS in promoting RTK signaling in GBM, we generated neural progenitor cells deficient for HS by knockout of the essential HS-biosynthetic enzyme Ext1, and studied tumor initiation and progression. HS-null cells had decreased proliferation, invasion, and reduced activation of multiple RTKs compared with control. In vivo tumor establishment was significantly decreased, and rate of tumor growth reduced with HS-deficient cells implanted in an HS-poor microenvironment. To investigate if HS regulates RTK activation through platelet-derived growth factor receptor α (PDGFRα) signaling, we removed cell surface HS in patient-derived GBM lines and identified reduced cell surface PDGF-BB ligand. Reduced ligand levels were associated with decreased phosphorylation of PDGFRα, suggesting HS promotes ligand–receptor interaction. Using human GBM tumorspheres and a murine GBM model, we show that ligand-mediated signaling can partially rescue cells from targeted RTK inhibition and that this effect is regulated by HS. Indeed, tumor cells deficient for HS had increased sensitivity to EGFR inhibition in vitro and in vivo. Implications: Our study shows that HS expressed on tumor cells and in the tumor microenvironment regulates ligand-mediated signaling, promoting tumor cell proliferation and invasion, and these factors contribute to decreased tumor cell response to targeted RTK inhibition.

It has been suggested that immunogenic cell death (ICD) has therapeutic potential; however, its anticancer immunity is considerably hampered by the in situ immunosuppressive microenvironment within the tumor area, such as the dysfunction of antigen-presenting cells. Herein, we present an in vitro ICD-inducing modality to circumvent such impairment of immune activation. To this end, a "hot", i.e., immunogenic, whole tumor cell vaccine is generated in vitro and subcutaneously vaccinated in the normal tissue, departing from the site of the in situ immunosuppressive tumor area, to fully leverage the ICD-inducing antitumor immunity. In particular, the immunogenic dying tumor cells, caged by cellular disulfide-thiol exchange, are mediated by photoactivation. After subcutaneous vaccination, the photoactivated caged live cell vaccine (CLCV) exerts multi-durable immunostimulatory property, which, when adjuvanted by CpG, efficiently promotes dendritic cell (DC) activation and elicits robust CD8+ T-cell responses in vivo. Importantly, the generated T-cell responses are shown to protect 75% mice preimmunized with CLCV against tumor initiation and significantly retards tumor growth in the therapeutic setting. The strategy presented here may help to enrich the current vaccine design for cancer immunotherapy.

Cancer is one of the most catastrophic human genetic diseases. Experimental animal cancer models are essential for gaining insights into the complex interactions of different cells and genes in tumor initiation, promotion, and progression. Mouse models have been extensively used to analyze the genetic basis of cancer susceptibility. They have led to the identification of multiple loci that confer, either alone or in specific combinations, an increased susceptibility to cancer, some of which have direct translatability to human cancer. Additionally, wild-derived inbred mouse strains are an advantageous reservoir of novel genetic polymorphisms of cancer susceptibility genes, because of the evolutionary divergence between wild and classical inbred strains. Here, we review mapped Stmm (skin tumor modifier of MSM) loci using a Japanese wild-derived inbred mouse strain, MSM/Ms, and describe recent advances in our knowledge of the genes responsible for Stmm loci in the 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) two-stage skin carcinogenesis model.

RAS genes are the most commonly mutated in human cancers and play critical roles in tumor initiation, progression, and drug resistance. Identification of targets that block RAS signaling is pivotal to develop therapies for RAS-related cancer. As RAS translocation to the plasma membrane (PM) is essential for its effective signal transduction, we devised a high-content screening assay to search for genes regulating KRAS membrane association. We found that the tyrosine phosphatase PTPN2 regulates the plasma membrane localization of KRAS. Knockdown of PTPN2 reduced the proliferation and promoted apoptosis in KRAS-dependent cancer cells, but not in KRAS-independent cells. Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. Consistently, analysis of the TCGA database demonstrates that high expression of PTPN2 is significantly associated with poor prognosis of patients with KRAS-mutant pancreatic adenocarcinoma. These results indicate that PTPN2 is a key regulator of KRAS and may serve as a new target for therapy of KRAS-driven cancer.

Objective: Esophageal squamous cell carcinoma (ESCC) has high morbidity and mortality rates worldwide. Cancer stem cells(CSCs) may cause tumor initiation, metastasis, and recurrence and are also responsible for chemotherapy and radiotherapy failures.Myeloid-derived suppressor cells (MDSCs), in contrast, are known to be involved in mediating immunosuppression. Here, we aimedto investigate the mechanisms of interaction of CSCs and MDSCs in the tumor microenvironment. Methods: ESCC tissues and cell lines were evaluated. Neural precursor cell expressed, developmentally downregulated 9 (NEDD9)was knocked down and overexpressed by lentiviral transfection. Quantitative PCR, Western blot, immunohistochemistry, cellinvasion, flow cytometry, cell sorting, multiplex chemokine profiling, and tumor growth analyses were performed. Results: Microarray analysis revealed 10 upregulated genes in esophageal CSCs. Only NEDD9 was upregulated in CSCs using thesphere-forming method. NEDD9 expression was correlated with tumor invasion (P = 0.0218), differentiation (P = 0.0153), andpoor prognosis (P = 0.0373). Additionally, NEDD9 was required to maintain the stem-like phenotype. Screening of chemokineexpression in ESCC cells with NEDD9 overexpression and knockdown showed that NEDD9 regulated C-X-C motif chemokineligand 8 (CXCL8) expression via the ERK pathway. CXCL8 mediated the recruitment of MDSCs induced by NEDD9 in vitro andin vivo. MDSCs promoted the stemness of ESCC cells through NEDD9 via the Notch pathway. Conclusions: As a marker of ESCC, NEDD9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathwayto recruit MDSCs into the tumor, suggesting NEDD9 as a therapeutic target and novel prognostic marker for ESCC.

Angiogenesis driven tumor initiation and progression calls for a targeted therapy. Moreover, combined chemotherapy supplements the therapy to act on the cause of concern. In this study, we aimed to develop a targeted crystalsomes approach to delineate tumor cells against normal cells. Self-assembled crystalline monodispersed nanosized polyethylene-polyethylene glycol (PE-PEG)-based hollow crystalsomes were modified with pluronylated putrescine (Put-PF) and loaded with doxorubicin (Dox), synergistically in combination with oleanolic acid (OA) to target the glypican-1 (gp-1) receptor on tumor cells. The developed crystalsomes (Put-D + O@NCs) showed increased intracellular accumulation of Dox and OA in a synergistic combination inside the MDA-MB-231 cell lines. The developed crystalsomes marked an enhanced depolarization of the mitochondrial membrane potential and cell cycle arrest leading to apoptosis. Furthermore, the proposed therapy has a greater anti-angiogenesis activity with vascular endothelial growth factor (VEGF) dependent modulation in the proliferation, invasion, migration and tube formation of human endothelial umbilical vein cells (HUVECs) in vitro and in vivo in a BALB/c mouse model. Interestingly, the perseverance of the tumor boundary, inhibiting the expression and activity of the matrix metalloproteinase (MMPs) (>5.2-fold) with suppressed degradation of the extracellular matrix paves the way for significant inhibition of metastases. However, an intravenously administered Put-D + O@NCs showed an improved pharmacokinetic profile and exquisite inhibition of the 4T1 induced tumor with a significantly lower toxicity. In a nutshell, these findings highlight the important role of Put in the gp-1 receptor for specific targeting and synergistic delivery of Dox and OA through crystalsomes as a potential approach for the treatment of metastatic breast cancer using combined chemotherapy.

Glutathione (GSH), the main redox buffer, has long been recognized as a pivotal modulator of tumor initiation, progression and metastasis. It is also implicated in the resistance of platinum-based chemotherapy and radiation therapy. Therefore, depleting intracellular GSH was considered a potent solution to combating cancer. However, reducing GSH within cancer cells alone always failed to yield desirable therapeutic effects. In this regard, the convergence of GSH-scavenging agents with therapeutic drugs has thus been pursued in clinical practice. Unfortunately, the therapeutic outcomes are still unsatisfactory due to untargeted drug delivery. Advanced nanomedicine of synergistic GSH depletion and cancer treatment has attracted tremendous interest because they promise to deliver superior therapeutic benefits while alleviating life-threatening side effects. In the past five years, the authors and others have demonstrated that numerous nanomedicines, by simultaneously delivering GSH-depleting agents and therapeutic components, boost not only traditional chemotherapy and radiotherapy but also multifarious emerging treatment modalities, including photodynamic therapy, sonodynamic therapy, chemodynamic therapy, ferroptosis, and immunotherapy, to name a few, and achieved decent treatment outcomes in a large number of rodent tumor models. In this review, we summarize the most recent progress in engineering nanomedicine for GSH depletion-enhanced cancer therapies. Biosynthesis of GSH and various types of GSH-consuming strategies will be briefly introduced. The challenges and perspectives of leveraging nanomedicine for GSH consumption-augmented cancer therapies will be discussed at the end.

Hepatocellular carcinoma (HCC) is considered as a common malignancy worldwide. Considerable evidence has illustrated that abnormally expressed long noncoding RNAs (lncRNAs) are in a close correlation with the initiation and progression of various tumors, including HCC. LncRNA small nucleolar RNA host gene 22 (SNHG22) has been reported to play important roles in tumor initiation, but its role and mechanism are little known in HCC. In our report, we discovered the high level of SNHG22 in HCC tissues and cells, and the high expression of SNHG22 was correlated with unfavorable clinical outcome in HCC patients. Functional assays implied that SNHG22 deficiency suppressed cell proliferation, migration, invasion, and angiogenesis in vitro. Additionally, it was also confirmed that silenced SNHG22 suppressed tumor growth and angiogenesis in vivo. Mechanistic exploration revealed that SNHG22 recruited DNMT1 to miR-16-5p DNA promoter through EZH2 and inhibited miR-16-5p transcription via DNA methylation. Finally, we verified that the suppression of miR-16-5p countervailed the suppressive effect of SNHG22 deficiency on HCC cell proliferation, migration, invasion, and angiogenesis. Conclusively, this study clarified the SNHG22/EZH2/DNMT1/miR-16-5p axis and revealed that SNHG22 could be an underlying biomarker for HCC.

Glioma cells with stem cell-like properties are crucial for tumor initiation, progression and therapeutic resistance. Therefore, identifying specific factors in regulating stem-like traits is critical for the design of novel glioma therapeutics. Herein, we reported that ADP-Ribosylation Factor Like GTPase 4C (ARL4C) was highly expressed in glioma stem-like cells (GSLCs). GSLCs, determined by the efficiency of sphere formation in vitro and tumor growth in vivo, was increased by overexpression of ARL4C. ARL4C induced the tumorigenesis through ALDH1A3. Analyses of 325 patient specimens showed that ARL4C was highly expressed in glioblastoma (GBM) as compared with lower grade gliomas. In addition, higher level ARL4C expression in glioma was correlated with poorer progression-free survival and overall survival of patients. Therefore, ARL4C may act as a novel prognostic marker and a therapeutic target for GBM.

Our objective is the calibration of mathematical tumor growth models from a single multiparametric scan. The target problem is the analysis of preoperative Glioblastoma (GBM) scans. To this end, we present a fully automatic tumor-growth calibration methodology that integrates a single-species reaction-diffusion partial differential equation (PDE) model for tumor progression with multiparametric Magnetic Resonance Imaging (mpMRI) scans to robustly extract patient specific biomarkers i.e., estimates for ( i ) the tumor cell proliferation rate , ( ii ) the tumor cell migration rate , and ( iii ) the original, localized site(s) of tumor initiation . Our method is based on a sparse reconstruction algorithm for the tumor initial location (TIL). This problem is particularly challenging due to nonlinearity, ill-posedeness, and ill conditioning. We propose a coarse-to-fine multi-resolution continuation scheme with parameter decomposition to stabilize the inversion. We demonstrate robustness and practicality of our method by applying the proposed method to clinical data of 206 GBM patients. We analyze the extracted biomarkers and relate tumor origin with patient overall survival by mapping the former into a common atlas space. We present preliminary results that suggest improved accuracy for prediction of patient overall survival when a set of imaging features is augmented with estimated biophysical parameters. All extracted features, tumor initial positions, and biophysical growth parameters are made publicly available for further analysis. To our knowledge, this is the first fully automatic scheme that can handle multifocal tumors and can localize the TIL to a few millimeters.

Active c-Src non-receptor tyrosine kinase localizes to the plasma membrane via N-terminal lipid modification. Membranous c-Src causes cancer initiation and progression. Even though transmembrane 4 L six family member 5 (TM4SF5), a tetraspan(in), can be involved in this mechanism, the molecular and structural influence of TM4SF5 on c-Src remains unknown. Methods: Here, we investigated molecular and structural details by which TM4SF5 regulated c-Src devoid of its N-terminus and how cell-penetrating peptides were able to interrupt c-Src activation via interference of c-Src-TM4SF5 interaction in hepatocellular carcinoma models. Results: The TM4SF5 C-terminus efficiently bound the c-Src SH1 kinase domain, efficiently to the inactively-closed form. The complex involved protein tyrosine phosphatase 1B able to dephosphorylate Tyr530. The c-Src SH1 domain alone, even in a closed form, bound TM4SF5 to cause c-Src Tyr419 and FAK Y861 phosphorylation. Homology modeling and molecular dynamics simulation studies predicted the directly interfacing residues, which were further validated by mutational studies. Cell penetration of TM4SF5 C-terminal peptides blocked the interaction of TM4SF5 with c-Src and prevented c-Src-dependent tumor initiation and progression in vivo. Conclusions: Collectively, these data demonstrate that binding of the TM4SF5 C-terminus to the kinase domain of inactive c-Src leads to its activation. Because this binding can be abolished by cell-penetrating peptides containing the TM4SF5 C-terminus, targeting this direct interaction may be an effective strategy for developing therapeutics that block the development and progression of hepatocellular carcinoma.

Bo Huang,1,* Zhichun Feng,2,3,* Lina Zhu,2 Sheng Zhang,2,3 Jun Duan,4 Chaochao Zhao,1 Xiaoying Zhang1,2 1Public Health, Guilin Medical University, Guilin 541100, People’s Republic of China; 2Affiliated BaYi Children’s Hospital, Seventh Medical Center of PLA General Hospital, Beijing 100700, People’s Republic of China; 3Beijing Key Laboratory of Pediatric Organ Failure, Beijing 100700, People’s Republic of China; 4Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoying ZhangPublic Health, Guilin Medical University, 1 Zhiyuan Road, Lingui District, Guilin 541100, People’s Republic of ChinaTel/Fax +86773-3680605Email xiaoyingzhang79@163.comPurpose: Mesenchymal stem cells (MSCs) are largely studied for their potential clinical use. Recently, there has been gained further interest in the relationship between MSCs and tumorigenesis. MSCs are reported to both promote and abrogate tumor growth. The present study was designed to investigate whether miRNAs are involved in the interactions between MSCs and tumor cells in the tumor microenvironment.Materials and Methods: Rat bone marrow-derived MSCs (rMSCs) were cultured with or without tumor-conditioned medium (TCM) to observe the effect upon MSCs by TCM. Microarrays and real-time PCR were performed between the two groups. A series of experiments were used to reveal the functional significance of microRNA-503 (miR-503) in rMSCs. Furthermore, the antitumorigenic effect of silencing of miR-503 in rMSCs (miR-503-i-rMSCs) in vivo was measured.Results: We found that rMSCs in vitro exhibited tumor-promoting properties in TCM, and the microRNA profiles of rMSCs were significantly altered in TCM. However, miR-503-i-rMSCs can decrease the angiogenesis and growth of A549 cells. We also demonstrated in an in vivo tumor model that miR-503-i-rMSCs inhibited A549 tumor angiogenesis and significantly abrogated tumor initiation and growth. CD133 assays in peripheral blood and A549 xenografts further validated that miR-503-i-rMSCs, rather than rMSCs, exerted an antitumorigenic action in the A549 tumor model.Conclusion: Our results suggest that miR-503-i-rMSCs are capable of tumor suppression. Further studies are required to develop clinical therapies based on the inhibition of the tumor-promoting properties and potentiation of the anti-tumor properties of MSCs.Keywords: mesenchymal stem cells, microRNA-503, tumor-conditioned medium, tumor angiogenesis

Accumulating evidence indicates that obesity with its associated metabolic dysregulation, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Caloric restriction can ameliorate the harmful metabolic effects of obesity and inhibit cancer progression but is difficult to implement and maintain outside of the clinic. In this study, we aim to test a time-restricted feeding (TRF) approach on mouse models of obesity-driven postmenopausal breast cancer. We show that TRF abrogates the obesity-enhanced mammary tumor growth in two orthotopic models in the absence of calorie restriction or weight loss. TRF also reduces breast cancer metastasis to the lung. Furthermore, TRF delays tumor initiation in a transgenic model of mammary tumorigenesis prior to the onset of obesity. Notably, TRF increases whole-body insulin sensitivity, reduces hyperinsulinemia, restores diurnal gene expression rhythms in the tumor, and attenuates tumor growth and insulin signaling. Importantly, inhibition of insulin secretion with diazoxide mimics TRF whereas artificial elevation of insulin through insulin pumps implantation reverses the effect of TRF, suggesting that TRF acts through modulating hyperinsulinemia. Our data suggest that TRF is likely to be effective in breast cancer prevention and therapy., Obesity and its associated metabolic changes, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Here, the authors show that restricting when mice eat, but not what or how much they eat, delays breast cancer initiation and reduces tumor growth in obese mice in addition to improving insulin sensitivity and restoring circadian rhythms.

Hepatocellular carcinoma (HCC) is a malignant tumor with poor prognosis, and is one of the leading causes of cancer-related deaths worldwide. Recently, the development of therapeutic drugs via novel mechanisms of action, involving molecular-targeted drugs and immune checkpoint inhibitors, has progressed in the field of HCC. However, the recurrence rate remains high, and further improvement of the prognosis of patients with HCC is urgently needed. Cancer stem cells (CSCs) are a promising target for further development of novel anti-cancer drugs because they are reportedly involved in tumor initiation, maintenance, recurrence, and resistance to conventional therapies. Although several studies have already been conducted, the functions and roles of CSCs in the development and progression of tumors remain to be elucidated. In this review article, we will clarify the fundamental knowledge of CSCs necessary for the understanding of CSCs and will outline so-far identified markers specific to liver CSCs and the pathological and therapeutic implications of CSCs in HCC.

With the highest incidence, breast cancer is the leading cause of cancer deaths among women in the world. Tumor metastasis is the major contributor of high mortality in breast cancer, and the existence of cancer stem cells (CSCs) has been proven to be the cause of tumor metastasis. CSCs are a small proportion of tumor cells, and they are associated with self-renewal and tumorigenic potential. Given the significance of CSCs in tumor initiation, expansion, relapse, resistance, and metastasis, studies should investigate and discover effective anticancer agents that can not only inhibit the proliferation of differentiated tumor cells but also reduce the tumorigenic capability of CSCs. Thus, new therapies must be discovered to treat and prevent this severely hazardous disease of human beings. The success of platinum complexes in cancer treatment has laid the basic foundation for the utilization of metal complexes in the treatment of malignant cancers, in particular the highly aggressive triple-negative breast cancer. Importantly, metal complexes currently have diverse and versatile competences in the therapeutic targeting of CSCs. The anti-CSC properties provide a strong impetus for the development of novel metal-based compounds for the targeting of CSCs and treatment of chemotherapy-resistant and relapsed tumors. In this review, we provide the latest advances in metal complexes including platinum, ruthenium, osmium, iridium, manganese, cobalt, nickel, copper, zinc, palladium, and tin complexes against breast CSCs obtained over the past decade, with pertinent literature including those published until 2021.

Advances in immunotherapy have led to durable and long‐term benefits in a subset of patients across a number of solid tumor types. Understanding of the subsets of patients that respond to immune checkpoint inhibitors at the cellular level, and in the context of their tumor microenvironment (TME) is becoming increasingly important. The TME is composed of a heterogeneous milieu of tumor and immune cells. The immune landscape of the TME can inhibit or promote tumor initiation and progression; thus, a deeper understanding of tumor immunity is necessary to develop immunotherapeutic strategies. Recent developments have focused on characterizing the TME immune contexture (type, density, and function) to discover mechanisms and biomarkers that may predict treatment outcomes. This has, in part, been powered by advancements in spatial characterization technologies. In this review article, we address the role of specific immune cells within the TME at various stages of tumor progression and how the immune contexture determinants affecting tumor growth are used therapeutically.

Gastric cancer (GC) is one of the most common malignancies and the second leading cause of cancer‑associated death in the world. The carcinogenesis and development of GC involves complicated steps and various factors, in which the tumor microenvironment serves a vital role. Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, are multipotent stromal cells, and have gained increasing attention due to their wound‑healing ability, as well as their tumor‑promoting potential. MSCs are essential components of the tumor microenvironment and serve important roles in tumor initiation, progression and metastasis. The present review focuses on GC and discusses recent advances in understanding the effect of GC‑derived MSC‑like cells (GC‑MSCs) on tumor progression, chemoresistance and immune escape. Additionally, the mechanism underlying the tumor tropism of bone marrow‑derived MSCs and the malignant transition of these cells to GC‑MSCs are addressed. The potential of GC‑MSCs in the treatment of GC, such as for predicting prognosis and as therapeutic targets, is also discussed in association with their critical role in tumor progression. The information on the characteristics and functions of GC‑MSCs provided in the present review may promote the development of novel therapeutic strategies against GC.

As a pleiotropic cytokine, interleukin-6 (IL-6) not only regulates the cellular immune response, but it also promotes tumor development by activating multiple carcinogenic pathways. IL-6 expression is significantly elevated in colorectal cancer (CRC) and is closely related to CRC development and patient prognosis. In CRC, IL-6 activates signal transducers and activators of transduction-3 (STAT3) to promote tumor initiation and tumor growth. IL-6/STAT3 signalling has a profound effect on tumor-infiltrating immune cells in the tumor immune microenvironment in CRC. Additionally, IL-6/STAT3 pathway activates downstream target genes to protect tumor cells from apoptosis; drive tumor cell proliferation, cell cycle progression, invasion and metastasis; promote tumor angiogenesis; and stimulate drug resistance. Therefore, a thorough understanding of the many effects of the IL-6/STAT3 pathway in CRC is needed, which the present review examines.

Our understanding of cancer-specific metabolic changes is currently unclear. In recent years, the fruit fly Drosophila melanogaster with its powerful genetic tools has become an attractive model for studying both tumor autonomous and the systemic processes resulting from the tumor growth. Here we investigated the effect of tumorigenesis on the modulation of lipid droplets (LDs) in the larval fat bodies (mammalian equivalent of adipose tissue). We have overexpressed Notch signaling alone or in combination with the developmental regulator Myocyte enhancer factor 2 (Mef2) using wing-specific and eye-specific drivers, quantified the size of LDs in the fat body of the different tumor bearing larvae, and estimated the expression of genes associated with lipolysis and lipogenesis. We have found that hyperplastic and neoplastic tumor induced by overexpression of Notch and co-expression of Notch and Mef2 respectively triggers impaired lipid metabolism marked by increased size of fat body LDs. The impaired lipid metabolism in tumor carrying larvae is linked to the altered expression of genes that participate in lipolysis and lipogenesis. These findings reveal modulation of LDs as one of the host’s specific response upon tumor initiation. This information could potentially uncover mechanisms for designing innovative approaches to modulate cancer growth.

In cancer cells, a gain of stemness may have profound implications for tumor initiation, aggressiveness, and clinical outcome. However, the molecular mechanisms underlying the self-renewal maintenance of cancer stem-like cells (CSCs) remain elusive. Here, based on analysis of transcriptome sequencing, we identified a long noncoding RNA (lncRNA) named HotairM1, which is weakly expressed in human colorectal carcinoma and uveal melanoma, and a much lower expression in corresponding CSCs. Our results showed that HotairM1 depletion could promote CSC self-renewal and tumor propagation. Mechanistically, HotairM1 recruit EZH2 and SUZ12 to the promoter of its target gene HOXA1, leading to histone H3K27 trimethylation and epigenetic silencing of HOXA1. The silence of HOXA1 subsequently induces the H3K27 acetylation at the enhancer site of Nanog gene to upregulate its expression. The enrichment of Nanog could further inhibit HOXA1 expression, forming a reciprocal regulation loop augmenting the stemness maintaining effect. In summary, our results revealed a lncRNA-based regulatory loop that sustains self-renewal of CSCs, which highlights the critical role of HotairM1 in CSC development through the HOXA1-Nanog signaling loop., Graphical Abstract, Knockdown of lncRNA HotairM1 could promote self-renewal of CSCs and subsequent tumor proliferation and propagation through inhibiting neighbor gene HOXA1 expression. HOXA1 would repress stemness maintenance of CSC through inhibiting Nanog expression.

Signal transducer and activator of transcription 3 (STAT3) is considered a potential target for cancer treatment because of its relationship with cellular transformation and tumor initiation and progression. In this study, we aimed to identify a new anti-cancer drug candidate from natural products by targeting STAT3 activity. Using STAT3-luciferase reporter cell line, we screened the chemical library of natural products and found that baicalein, a flavone isolated from the roots of Scutelleria baicalensis, strongly suppressed STAT3 activity in breast cancer cells. Baicalein inhibited STAT3 transcriptional activity and its phosphorylation, and further exhibited anti-proliferative effects in breast cancer cells. Moreover, baicalein suppressed the production of interleukin (IL)-6 and the metastatic potential of breast cancer cells both in vitro and in vivo. Collectively, our study suggests baicalein as an attractive phytochemical compound for reducing metastatic potential of breast cancer cells by regulating STAT3 activity.