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Glycogen-storing so-called clear cell kidney tubules (CCTs), precursor lesions of renal cell carcinoma, have been described in diabetic rats and in humans. The lesions show upregulation of the Akt/mTOR-pathway and the related transcription factor carbohydrate responsive element binding protein (ChREBP), which is supposedly pro-oncogenic. We investigated the effect of ChREBP-knockout on nephrocarcinogenesis in streptozotocin-induced diabetic and normoglycemic mice. Diabetic, but not non-diabetic mice, showed CCTs at 3, 6 and 12 months of age. Glycogenosis was confirmed by periodic acid schiff reaction and transmission electron microscopy. CCTs in ChREBP-knockout mice consisted of larger cells and occurred more frequently compared to wildtype mice. Progression towards kidney tumors was observed in both diabetic groups but occurred earlier in ChREBP-knockout mice. Proliferative activity assessed by BrdU-labeling was lower in 1-week-old but higher in 12-month-old diabetic ChREBP-knockout mice. Surprisingly, renal neoplasms occurred spontaneously in non-diabetic ChREBP-knockout, but not non-diabetic wildtype mice, indicating an unexpected tumor-suppressive function of ChREBP. Immunohistochemistry showed upregulated glycolysis and lipogenesis, along with activated Akt/mTOR-signaling in tumors of ChREBP-knockout groups. Immunohistochemistry of human clear cell renal cell carcinomas revealed reduced ChREBP expression compared to normal kidney tissue. However, the molecular mechanisms by which loss of ChREBP might facilitate tumorigenesis require further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Stromal cells and growth factors play important roles during tumor initiation and progression. Growth factors not only mediate normal biological processes such as development and tissue repair but also tumorigenesis by contributing to tumor growth and the transformation of neoplastic cells. This study investigated the host angiogenic and proinflammatory cytokines during tumor initiation and progression in heterotopic xenografts of MiaPaCa-2-eGFP tumors growing in RAGxCγ double mutant mice. Tumor vasculature requires stringently balanced angiogenic cytokine signaling to provide sufficient vasculature for tumor development. Notably, the mechanism(s) that cause(s) tumors to develop and continuously interact with the tumor microenvironment (TME) and other host systems still need to be investigated. The TME is a complex environment that surrounds and interacts with tumors. The TME generally also includes tumor stroma and immune cells within the tumor node. It is true, though, that tumor cells are embedded in the TME. From a cellular perspective, the TME allows cancerous cells to progress and develop through features such as stromal cells, fibroblasts, endothelial cells, and adipocytes. These components can involve contemporaneous inflammatory and angiogenic cytokine profiles that propitiously prompt tumor survival, local invasion, and metastatic dispersion. Cytokines can promote various cancer processes, such as angiogenesis, epithelial to mesenchymal transition (EMT), invasion, and tumor progression, and maintain cancer stem-cell-like (CSCs) cells. The mechanism(s) that continuously promote(s) tumors to progress in the TME still need(s) to be investigated. The data in the present study analyzed the inflammatory, angiogenic, fibrogenic, and angiostatic cytokine profiles in the host serum during tumor development in a mouse model of human pancreatic cancer. Pancreatic MiaPaCa-2-eGFP cancer cells were subcutaneously implanted in RAG2xCγ double mutant mice. Blood samples were collected before cancer cell implantation and every week until the end point of the study. The extracted serum from the blood of each mouse at different time points during tumor development was analyzed using a Bio-Plex microarray analysis and a Bio-Plex 200 system for proinflammatory (IL-1β, IL-10, IFN-γ, and TNF-α) and angiogenic and fibrogenic (IL-15, IL-18, basic FGF, LIF, M-CSF, MIG, MIP-2, PDGF-BB, and VEGF) cytokines. Here, we find that during cancer cell colonization for tumor development, host angiogenic, fibrogenic, and proinflammatory cytokine profiling in the tumor-bearing mice has been shown to significantly reduce host angiostatic and proinflammatory cytokines that restrain tumor development and increase those for tumor growth. The proinflammatory cytokines IL-15, IL-18, and IL-1β profiles reveal a significant host serum increase after day 35 when the tumor began to progress in growth. In contrast, the angiostatic cytokine profiles of TNFα, MIG, M-CSF, IL-10, and IFNγ in the host serum revealed a dramatic and significant decrease after day 5 post-implantation of cancer cells. OP treatment of tumor-bearing mice on day 35 maintained high levels of angiostatic and fibrogenic cytokines. The data suggest an entirely new regulation by cancer cells for tumor development. The findings identify for the first time how pancreatic cancer cells use host cytokine profiling to orchestrate the initiation of tumor development. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) arises from aberrant mutations in colorectal cells, frequently linked to chronic inflammation. This study integrated human gut metagenome analysis with an azoxymethane and dextran sulfate sodium-induced CRC mouse model to investigate the dynamics of inflammation, gut microbiota, and metabolomic profiles throughout tumorigenesis. The analysis of stool metagenome data from 30 healthy individuals and 40 CRC patients disclosed a significant escalation in both gut microbiota diversity and abundance in CRC patients compared to healthy individuals (p < 0.05). Marked structural disparities were identified between the gut microbiota of healthy individuals and those with CRC (p < 0.05), characterized by elevated levels of clostridia and diminished bifidobacteria in CRC patients (p < 0.05). In the mouse model, CRC mice exhibited distinct gut microbiota structures and metabolite signatures at early and advanced tumor stages, with subtle variations noted during the intermediate phase. Additionally, inflammatory marker levels increased progressively during tumor development in CRC mice, in contrast to their stable levels in healthy counterparts. These findings suggest that persistent inflammation might precipitate gut dysbiosis and altered microbial metabolism. Collectively, this study provides insights into the interplay between inflammation, gut microbiota, and metabolite changes during CRC progression, offering potential biomarkers for diagnosis. While further validation with larger cohorts is warranted, the data obtained support the development of CRC prevention and diagnosis strategies. [ABSTRACT FROM AUTHOR]

Background: Immune stressors, such as lipopolysaccharides (LPS), profoundly affect microbiota balance, leading to gut dysbiosis. This imbalance disrupts the metabolic phenotype and structural integrity of the gut, increasing intestinal permeability. During puberty, a critical surge in estrogen levels is crucial for mammary gland development. However, inflammation originating from the gut in this period may interfere with this development, potentially heightening breast cancer risk later. The long‐term effects of pubertal inflammation on mammary development and breast cancer risk are underexplored. Such episodes can dysregulate cytokine levels and microRNA expression, altering mammary cell gene expression, and predisposing them to tumorigenesis. Methods: This study hypothesizes that prebiotics, specifically Lentinula edodes Cultured Extract (AHCC), can counteract LPS's adverse effects. Using BALB/c mice, an acute LPS dose was administered at puberty, and breast cancer predisposition was assessed at 13 weeks. Cytokine and tumor‐related microRNA levels, tumor development, and cancer stem cells were explored through immunoassays and qRT‐PCR. Results: Results show that LPS induces lasting effects on cytokine and microRNA expression in mammary glands and tumors. AHCC modulates cytokine expression, including IL‐1β, IL‐17A/F, and IL‐23, and mitigates LPS‐induced IL‐6 in mammary glands. It also regulates microRNA expression linked to tumor progression and suppression, particularly counteracting the upregulation of oncogenic miR‐21, miR‐92, and miR‐155. Although AHCC slightly alters some tumor‐suppressive microRNAs, these changes are modest, highlighting a complex regulatory role that warrants further study. Conclusion: These findings underscore the potential of dietary interventions like AHCC to mitigate pubertal LPS‐induced inflammation on mammary gland development and tumor formation, suggesting a preventive strategy against breast cancer. [ABSTRACT FROM AUTHOR]

Sugar serves as the primary energy source for mammals, with glucose metabolism facilitating energy acquisition in human cells. The proper functioning of intracellular glucose metabolism is essential for the maintenance of orderly and healthy physiological activities. Tumor cells, characterized by uncontrolled growth, exhibit dysregulated proliferation and apoptosis processes, leading to abnormal alterations in glucose metabolism. Specifically, tumor cells exhibit a shift towards aerobic glycolysis, resulting in the production of lactic acid that can be utilized as a metabolic intermediate for sustained tumor cell growth. This article provides a comprehensive overview of the enzymes involved in glucose metabolism and the alterations in gene expression that occur during tumor progression. It also examines the current research on targeting abnormal glucose metabolism processes for tumor treatment and discusses potential future directions for utilizing glucose metabolism as a therapeutic target. [ABSTRACT FROM AUTHOR]

Abstract Lung cancer (LC) is the leading cause of cancer‐related death worldwide, with non‐small cell lung cancer (NSCLC) comprising 85% of all cases. COX‐2, an enzyme induced significantly under stress conditions, catalyzes the conversion of free arachidonic acid into prostaglandins. It exhibits high expression in various tumors and is closely linked to LC progression. COX‐2 functions as a pivotal driver in cancer pathogenesis by promoting prostaglandin E2 synthesis and facilitating tumor cell occurrence and development. Furthermore, COX‐2 holds potential as a predictive marker for early‐stage NSCLC, guiding targeted therapy in patients with early COX‐2 overexpression. Additionally, combining COX‐2 inhibitors with diverse treatment modalities enhances tumor therapeutic efficacy, minimizes adverse effects on healthy tissues, and improves overall patient survival rates posttreatment. In conclusion, combined therapy targeting COX‐2 presents a promising novel strategy for NSCLC treatment, offering avenues for improving prognosis and effective tumor treatment. This review provides novel insights and ideas for developing new treatment strategies to improve the prognosis of NSCLC.

Abstract Metabolic reprogramming has been demonstrated to have a significant impact on the biological behaviors of tumor cells, among which glycolysis is an important form. Recent research has revealed that the heightened glycolysis levels, the abnormal expression of glycolytic enzymes, and the accumulation of glycolytic products could regulate the growth, proliferation, invasion, and metastasis of tumor cells and provide a favorable microenvironment for tumor development and progression. Based on the distinctive glycolytic characteristics of tumor cells, novel imaging tests have been developed to evaluate tumor proliferation and metastasis. In addition, glycolytic enzymes have been found to serve as promising biomarkers in tumor, which could provide assistance in the early diagnosis and prognostic assessment of tumor patients. Numerous glycolytic enzymes have been identified as potential therapeutic targets for tumor treatment, and various small molecule inhibitors targeting glycolytic enzymes have been developed to inhibit tumor development and some of them are already applied in the clinic. In this review, we systematically summarized recent advances of the regulatory roles of glycolysis in tumor progression and highlighted the potential clinical significance of glycolytic enzymes and products as novel biomarkers and therapeutic targets in tumor treatment.

The plectin gene can encode a cytoskeletal linking protein, plectin, known for its interaction with three critical components of the cellular cytoskeleton: intermediate filaments, microtubules, and actin filaments. In recent years, more and more studies have reported that plectin is closely related to tumorigenesis and development, exhibiting both tumor-suppressive and tumor-promoting functions. Here, we first introduce the molecular structure and function of plectin, and then we summarize the current understanding of the crucial role of plectin in cancer progression. Finally, we also discuss the possible reasons for the different roles of plectin expression in various types of cancer and highlight the double-edged sword role of plectin in tumor progression. The review aims to deepen the comprehensive understanding of plectin's role in cancer and further help to develop novel therapeutic strategies and drug targets. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are known as unique professional antigen (Ag)-presenting cells (APCs) to prime naïve T cells for the initiation of adaptive immunity. While DCs are believed to play a pivotal role in generating antitumor T-cell responses, the importance of DCs in the protection from the progression of tumors remains elusive. Here, we show how the constitutive deficiency of CD11chi DCs influences the progression of tumors with the use of binary transgenic mice with constitutive loss of CD11chi DCs. Constitutive loss of CD11chi DCs not only enhances the progression of tumors but also reduces the responses of Ag-specific T cells. Furthermore, the congenital deficiency of CD11chi DCs generates the immunosuppressive tumor microenvironment (TME) that correlates with the marked accumulation of myeloid-derived suppressor cells (MDSCs) and the prominent productions of immunosuppressive mediators. Thus, our findings suggest that CD11chi DCs are crucial for generating anti-tumor T-cell responses and immunogenic TME to suppress the development of tumors. [ABSTRACT FROM AUTHOR]

The Warburg effect, first observed by Otto Warburg in the 1920s, delineates a metabolic phenomenon in which cancer cells exhibit heightened glucose uptake and lactate production, even under normoxic conditions. This metabolic shift towards glycolysis, despite the presence of oxygen, fuels the energy demands of rapidly proliferating cancer cells. Dysregulated glucose metabolism, characterized by the overexpression of glucose transporters and the redirection of metabolic pathways towards glycolysis, lies at the crux of this metabolic reprogramming. Consequently, the accumulation of lactate as a byproduct contributes to the creation of an acidic tumor microenvironment, fostering tumor progression and metastasis. However, recent research, notably proposed by Maher Akl, introduces a novel perspective regarding the role of glycolipids in cancer metabolism. Akl's glucolipotoxicity hypothesis posits that aberrant glycolipid metabolism, specifically the intracellular buildup of glycolipids, significantly influences tumor initiation and progression. This hypothesis underscores the disruptive impact of accumulated glycolipids on cellular homeostasis, thereby activating oncogenic pathways and promoting carcinogenesis. This perspective aims to synthesize the intricate mechanisms underlying both the Warburg effect and glucolipotoxicity, elucidating their collective contributions to tumor growth and malignancy. By comprehensively understanding these metabolic aberrations, novel avenues for therapeutic intervention targeting the fundamental drivers of cancer initiation and progression emerge, holding promise for more efficacious treatment strategies in the future. [ABSTRACT FROM AUTHOR]

Evidence indicates that chronic social stress plays a significant role in the development of cancer and depression. Although their association is recognized, the precise physiological mechanism remains unknown. In our previous work, we observed that OF1 males subjected to chronic social defiance exhibited anhedonia, and those who developed tumors in the lung showed anxiety-associated behaviors. In this study, we observed that tumor-bearing OF1 mice presented higher levels of 3-HK, and this increase may be due to IDO. No differences in hippocampal catecholamine levels were observed. Our results suggest that a systemic tumor can induce molecular changes in the hippocampal kynurenine pathway that may impact behavior.

Abstract The prevalence of papillary thyroid cancer (PTC) has been rising in recent years. Despite its relatively low mortality, PTC frequently metastasizes to lymph nodes and often recurs, posing significant health and economic burdens. The role of iodine in the pathogenesis and advancement of thyroid cancer remains poorly understood. Circular RNAs (circRNAs) are recognized to function as competing endogenous RNAs (ceRNAs) that modulate gene expression and play a role in various cancer stages. Consequently, this research aimed to elucidate the mechanism by which circRNA influences the impact of iodine on PTC. Our research indicates that high iodine levels can exacerbate the malignancy of PTC via the circ_0004851/miR-296-3p/FGF11 axis. These insights into iodine’s biological role in PTC and the association of circRNA with the disease could pave the way for novel biomarkers and potentially effective therapeutic strategies to mitigate PTC progression.

Abstract The relationship between the immune cell and tumor occurrence and progression remains unclear. Profiling alterations in the tumor immune microenvironment (TIME) at high resolution is crucial to identify factors influencing cancer progression and enhance the effectiveness of immunotherapy. However, traditional sequencing methods, including bulk RNA sequencing, exhibit varying degrees of masking the cellular heterogeneity and immunophenotypic changes observed in early and late-stage tumors. Single-cell RNA sequencing (scRNA-seq) has provided significant and precise TIME landscapes. Consequently, this review has highlighted TIME cellular and molecular changes in tumorigenesis and progression elucidated through recent scRNA-seq studies. Specifically, we have summarized the cellular heterogeneity of TIME at different stages, including early, late, and metastatic stages. Moreover, we have outlined the related variations that may promote tumor occurrence and metastasis in the single-cell era. The widespread applications of scRNA-seq in TIME will comprehensively redefine the understanding of tumor biology and furnish more effective immunotherapy strategies.

The prevalence of papillary thyroid cancer (PTC) has been rising in recent years. Despite its relatively low mortality, PTC frequently metastasizes to lymph nodes and often recurs, posing significant health and economic burdens. The role of iodine in the pathogenesis and advancement of thyroid cancer remains poorly understood. Circular RNAs (circRNAs) are recognized to function as competing endogenous RNAs (ceRNAs) that modulate gene expression and play a role in various cancer stages. Consequently, this research aimed to elucidate the mechanism by which circRNA influences the impact of iodine on PTC. Our research indicates that high iodine levels can exacerbate the malignancy of PTC via the circ_0004851/miR-296-3p/FGF11 axis. These insights into iodine's biological role in PTC and the association of circRNA with the disease could pave the way for novel biomarkers and potentially effective therapeutic strategies to mitigate PTC progression. [ABSTRACT FROM AUTHOR]

Glioma is a common primary malignant intracranial tumor. Existing treatment modalities have limitations,as high-grade glioma often remains incurable even after surgical intervention and radiochemotherapy. HES1 belongs to the basic helix-loop-helix(BHLH)family of transcription factors and plays a crucial role in cell development,differentiation and proliferation. The role of HES1 in the progression and worsening of glioma has garnered significant attention. This review aims to explore the mechanistic role of HES1 in glioma development and its impact on treatment modalities by reviewing relevant studies and summarizing advancements in this field. [ABSTRACT FROM AUTHOR]

The relationship between the immune cell and tumor occurrence and progression remains unclear. Profiling alterations in the tumor immune microenvironment (TIME) at high resolution is crucial to identify factors influencing cancer progression and enhance the effectiveness of immunotherapy. However, traditional sequencing methods, including bulk RNA sequencing, exhibit varying degrees of masking the cellular heterogeneity and immunophenotypic changes observed in early and late-stage tumors. Single-cell RNA sequencing (scRNA-seq) has provided significant and precise TIME landscapes. Consequently, this review has highlighted TIME cellular and molecular changes in tumorigenesis and progression elucidated through recent scRNA-seq studies. Specifically, we have summarized the cellular heterogeneity of TIME at different stages, including early, late, and metastatic stages. Moreover, we have outlined the related variations that may promote tumor occurrence and metastasis in the single-cell era. The widespread applications of scRNA-seq in TIME will comprehensively redefine the understanding of tumor biology and furnish more effective immunotherapy strategies. [ABSTRACT FROM AUTHOR]

The nuclear factor-κB (NF-κB) family, consisting of several transcription factors, has been implicated in the regulation of cell proliferation and invasion, as well as inflammatory reactions and tumor development. Cervical cancer (CC) results from long-term interactions of multiple factors, among which persistent high-risk human papillomavirus (hrHPV) infection is necessary. During different stages from early to late after HPV infection, the activity of NF-κB varies and plays various roles in carcinogenesis and progress of CC. As the center of the cell signaling transduction network, NF-κB can be activated through classical and non-classical pathways, and regulate the expression of downstream target genes involved in regulating the tumor microenvironment and acquiring hallmark traits of CC cells. Targeting NF-κB may help treat CC and overcome the resistance to radiation and chemotherapy. Even though NF-κB inhibitors have not been applied in clinical treatment as yet, due to limitations such as dose-restrictive toxicity and poor tumor-specificity, it is still considered to have significant therapeutic potential and application prospects. In this review, we focus on the role of NF-κB in the process of CC occurrence and hallmark capabilities acquisition. Finally, we summarize relevant NF-κB-targeted treatments, providing ideas for the prevention and treatment of CC. [ABSTRACT FROM AUTHOR]

Cytokines can promote various cancer processes, such as angiogenesis, epithelial to mesenchymal transition (EMT), invasion, and tumor progression, and maintain cancer stem-cell-like (CSCs) cells. The mechanism(s) that continuously promote(s) tumors to progress in the TME still need(s) to be investigated. The data in the present study analyzed the inflammatory, angiogenic, fibrogenic, and angiostatic cytokine profiles in the host serum during tumor development in a mouse model of human pancreatic cancer. Pancreatic MiaPaCa-2-eGFP cancer cells were subcutaneously implanted in RAG2xCγ double mutant mice. Blood samples were collected before cancer cell implantation and every week until the end point of the study. The extracted serum from the blood of each mouse at different time points during tumor development was analyzed using a Bio-Plex microarray analysis and a Bio-Plex 200 system for proinflammatory (IL-1β, IL-10, IFN-γ, and TNF-α) and angiogenic and fibrogenic (IL-15, IL-18, basic FGF, LIF, M-CSF, MIG, MIP-2, PDGF-BB, and VEGF) cytokines. Here, we find that during cancer cell colonization for tumor development, host angiogenic, fibrogenic, and proinflammatory cytokine profiling in the tumor-bearing mice has been shown to significantly reduce host angiostatic and proinflammatory cytokines that restrain tumor development and increase those for tumor growth. The proinflammatory cytokines IL-15, IL-18, and IL-1β profiles reveal a significant host serum increase after day 35 when the tumor began to progress in growth. In contrast, the angiostatic cytokine profiles of TNFα, MIG, M-CSF, IL-10, and IFNγ in the host serum revealed a dramatic and significant decrease after day 5 post-implantation of cancer cells. OP treatment of tumor-bearing mice on day 35 maintained high levels of angiostatic and fibrogenic cytokines. The data suggest an entirely new regulation by cancer cells for tumor development. The findings identify for the first time how pancreatic cancer cells use host cytokine profiling to orchestrate the initiation of tumor development.

Adverse environmental and lifestyle factors produce considerable effects on occurrence of cancerous tumors, both directly and indirectly through impaired functionality of the body protection mechanisms. Investigation of these effects has practical significance for risk assessment and development of effective cancer preventive strategies. Mathematical modeling is an eligible method for considering complex multicomponent interactions between elements of various systems involved in tumor growth. This article presents an approach to assessing risks of cancerous tumors by using a created predictive model that describes dynamics of abnormal cells considering regulatory mechanisms and angiogenesis. An evolution approach is applied to estimate accumulated functional disorders of the immune system due to natural ageing and chemical environmental exposures. The Monte Carlo simulation is employed to estimate a likely outcome of cancerous tumor evolution given different possible properties of abnormal cells. The article provides the results of accomplished computation experiments aimed at describing dynamics of changes in cell population properties in an analyzed organ tissue. Development of a vessel system is described considering different effects of the most significant factors. Computation results are analyzed within various scenarios that describe cancerous tumor growth in dynamics considering how angiogenesis develops under different parameters of the immune system dysfunction and different properties of abnormal cells. Risks of tumor development are assessed considering parameters that determine the overall state of the body (the immune system) and properties of abnormal cells. This approach makes it possible to develop a system of preventive and sanitary-hygienic activities in areas where envi-ronmental conditions are unfavorable in order to reduce cancer incidence.

The plectin gene can encode a cytoskeletal linking protein, plectin, known for its interaction with three critical components of the cellular cytoskeleton: intermediate filaments, microtubules, and actin filaments. In recent years, more and more studies have reported that plectin is closely related to tumorigenesis and development, exhibiting both tumor-suppressive and tumor-promoting functions. Here, we first introduce the molecular structure and function of plectin, and then we summarize the current understanding of the crucial role of plectin in cancer progression. Finally, we also discuss the possible reasons for the different roles of plectin expression in various types of cancer and highlight the double-edged sword role of plectin in tumor progression. The review aims to deepen the comprehensive understanding of plectin’s role in cancer and further help to develop novel therapeutic strategies and drug targets.

Malignant tumor is still a major problem worldwide. During tumorigenesis or tumor development, tumor suppressor p53-binding protein 2 (TP53BP2), also known as apoptosis stimulating protein 2 of p53 (ASPP2), plays a critical role in p53 dependent and independent manner. Expression of TP53BP2 is highly correlated with the prognosis and survival rate of malignant tumor patients. TP53BP2 can interact with p53, NF-κB p65, Bcl-2, HCV core protein, PP1, YAP, CagA, RAS, PAR3, and other proteins to regulate cell function. Moreover, TP53BP2 can also regulate the proliferation, apoptosis, autophagy, migration, EMT and drug resistance of tumor cells through downstream signaling pathways, such as NF-κB, RAS/MAPK, mevalonate, TGF-β1, PI3K/AKT, aPKC-ι/GLI1 and autophagy pathways. As a potential therapeutic target, TP53BP2 has been attracted more attention. We review the role of TP53BP2 in tumorigenesis or tumor development and the signal pathway involved in TP53BP2, which may provide more deep insight and strategies for tumor treatment.

Triple-negative breast cancer (TNBC) is a biologically and clinically heterogeneous disease. The G protein-coupled estrogen receptor (GPER) plays a crucial role in mediating the effect of estrogen and estrogen-like compounds in TNBC cells. Compared with other subtypes, GPER has a higher expression in TNBC. The GPER mechanisms have been thoroughly characterized and analyzed in estrogen receptor α (ERα) positive breast cancer, but not in TNBC. Our previous work revealed that a higher expression of GPER mRNA indicates a better prognosis for ERα-positive breast cancer; however, its effects in TNBC differ. Whether GPER could serve as a predictive prognostic marker or therapeutic target for TNBC remains unclear. In this review, we provide a detailed introduction to the subcellular localization of GPER, the different effects of various ligands, and the interactions between GPER and closely associated factors in TNBC. We focused on the internal molecular mechanisms specific to TNBC and thoroughly explored the role of GPER in promoting tumor development. We also discussed the interaction of GPER with specific cytokines and chemokines, and the relationship between GPER and immune evasion. Additionally, we discussed the feasibility of using GPER as a therapeutic target in the context of existing studies. This comprehensive review highlights the effects of GPER on TNBC, providing a framework and directions for future research.

Neutrophils exert either pro- or anti-tumor activities. However, few studies have focused on neutrophils at the tumor initiation stage. In this study, we unexpectedly found a subcutaneous nodule in the groin areas of mice inoculated with tumor cells. The nodule was developed 24 h after the inoculation, filled with tumor cells and massively recruited neutrophils, being designated as tumor nodules. 22% of the neutrophils in tumor nodules are surface TLR9 (sTLR9) expressing neutrophils (sTLR9+ neutrophils). With tumor progression, sTLR9+ neutrophils were sustainably increased in tumor nodules/tumor tissues, reaching to 90.8% on day 13 after inoculation, with increased expression of IL-10 and decreased or no expression of TNFα. In vivo administration of CpG 5805 significantly reduced sTLR9 expression of the sTLR9+ neutrophils. The reduction of sTLR9 on neutrophils in tumor nodules contributed to the induction of an anti-tumor microenvironment conductive to the inhibition of tumor growth. Overall, the study provides insights for understanding the role of sTLR9+ neutrophils in the tumor development, especially in the early stage. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explains how the application of single-cell transcriptomics can enhance personalized cancer immunotherapy. Tumors exhibit complex and heterogeneous characteristics that can impede the effectiveness of immunotherapy. We specifically present the "Origin of Tumor Development" (OTD), consisting of undifferentiated tumor cells, which contribute to tumor diversity and heterogeneity. Using single-cell transcriptomics, scientists can analyze the gene expression profiles of individual tumor cells to gain insight into tumorigenesis, progression, and immune evasion. This approach enables the identification of personalized biomarkers and targets, including immune checkpoints and tumor-infiltrating lymphocytes, tailored to each patient. We also discuss future directions, such as the development of analytical tools and databases, to maximize the potential for targeting the patient's OTD cells and advance personalized cancer immunotherapy. Cancer immunotherapy is a promising approach for treating malignancies through the activation of anti-tumor immunity. However, the effectiveness and safety of immunotherapy can be limited by tumor complexity and heterogeneity, caused by the diverse molecular and cellular features of tumors and their microenvironments. Undifferentiated tumor cell niches, which we refer to as the "Origin of Tumor Development" (OTD) cellular population, are believed to be the source of these variations and cellular heterogeneity. From our perspective, the existence of distinct features within the OTD is expected to play a significant role in shaping the unique tumor characteristics observed in each patient. Single-cell transcriptomics is a high-resolution and high-throughput technique that provides insights into the genetic signatures of individual tumor cells, revealing mechanisms of tumor development, progression, and immune evasion. In this review, we explain how single-cell transcriptomics can be used to develop personalized cancer immunotherapy by identifying potential biomarkers and targets specific to each patient, such as immune checkpoint and tumor-infiltrating lymphocyte function, for targeting the OTD. Furthermore, in addition to offering a possible workflow, we discuss the future directions of, and perspectives on, single-cell transcriptomics, such as the development of powerful analytical tools and databases, that will aid in unlocking personalized cancer immunotherapy through the targeting of the patient's cellular OTD. [ABSTRACT FROM AUTHOR]

Ouabain (OUA) is a cardiotonic steroid with an immunomodulatory and anti-inflammatory role in different experimental models. Currently, the potential antineoplastic effect of OUA has been studied, however, research is needed to better understand OUA role during tumor development. Therefore, our aim was to investigate the OUA effects on Ehrlich tumor (ET) development in vitro and in vivo. To evaluate the cytotoxic effects of OUA on ET in vitro the cells were incubated with different concentrations of OUA during 24h and 48h and our results showed that only the [1000 ?M] decreased the number and viability of ET cells in the two analyzed times. To study the OUA effects on ET in vivo, Swiss mice were pretreated with 0.56 mg/kg of OUA intraperitoneally (i.p.) for three consecutive days. To develop ET in the solid form, one hour after the last day of pretreatment, ET cells were inoculated subcutaneously into the footpad and the animals were monitored for 13 days. To develop the ascitic form, ET cells were inoculated (i.p.) and the animals were monitored for 3 days. OUA was able to reduce the thickness and weight of the tumor paw, in addition to reduce the weight of the popliteal lymph node. In the ascitic tumor, OUA reduced the number of neutrophils and macrophages and increased the lymphocytes in the peritoneum. Thus, we demonstrated that OUA affects ET development both in vitro and in vivo. Our results suggest a new perspective in the anti-inflammatory, immunomodulatory and a possible anti-cancer role of ouabain and brings new concepts about the pathophysiological role of this substance.

Abstract Chronic stress results in disturbances of body hormones through the neuroendocrine system. Cancer patients often experience recurrent anxiety and restlessness during disease progression and treatment, which aggravates disease progression and hinders treatment effects. Recent studies have shown that chronic stress-regulated neuroendocrine systems secret hormones to activate many signaling pathways related to tumor development in tumor cells. The activated neuroendocrine system acts not only on tumor cells but also modulates the survival and metabolic changes of surrounding non-cancerous cells. Current clinical evidences also suggest that chronic stress affects the outcome of cancer treatment. However, in clinic, there is lack of effective treatment for chronic stress in cancer patients. In this review, we discuss the main mechanisms by which chronic stress regulates the tumor microenvironment, including functional regulation of tumor cells by stress hormones (stem cell-like properties, metastasis, angiogenesis, DNA damage accumulation, and apoptotic resistance), metabolic reprogramming and immune escape, and peritumor neuromodulation. Based on the current clinical treatment framework for cancer and chronic stress, we also summarize pharmacological and non-pharmacological therapeutic approaches to provide some directions for cancer therapy.

It has been confirmed that platelets play a key role in tumorigenesis. Tumoractivated platelets can recruit blood cells and immune cells to migrate, establish an inflammatory tumor microenvironment at the sites of primary and metastatic tumors. On the other hand, they can also promote the differentiation of mesenchymal cells, which can accelerate the proliferation, genesis and migration of blood vessels. The role of platelets in tumors has been well studied. However, a growing number of studies suggest that interactions between platelets and immune cells (e.g., dendritic cells, natural killer cells, monocytes, and red blood cells) also play an important role in tumorigenesis and tumor development. In this review, we summarize the major cells that are closely associated with platelets and discuss the essential role of the interaction between platelets with these cells in tumorigenesis and tumor development. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer (LC) represents the leading cause of cancer incidence and mortality worldwide. LC is a lung tumor associated with genetic mutations and environmental (tobacco smoking) or pathological conditions, with poor prognosis and a difficult pharmacological approach. TGF-β is a molecule that regulates different biological processes at a pulmonary level, and its alteration has been associated with LC development and metastasis. Despite advancements in knowledge of the molecular mechanisms involved in LC, this tumor is still characterized by an unfavorable prognosis and current therapeutic options are unsatisfactory. Some studies have demonstrated that TGF-β overexpression could be considered a potential predictive marker in LC prognosis, and TGF-β inhibition has been shown to prevent LC metastasis. Moreover, TGF-β inhibitors could be used in combination with chemo- and immunotherapy, thereby improving patient survival. Overall, targeting TGF-β may be a valid possibility to fight LC, and is a novel and effective strategy against this aggressive cancer. Lung cancer (LC) represents the leading cause of cancer incidence and mortality worldwide. LC onset is strongly related to genetic mutations and environmental interactions, such as tobacco smoking, or pathological conditions, such as chronic inflammation. Despite advancement in knowledge of the molecular mechanisms involved in LC, this tumor is still characterized by an unfavorable prognosis, and the current therapeutic options are unsatisfactory. TGF-β is a cytokine that regulates different biological processes, particularly at the pulmonary level, and its alteration has been demonstrated to be associated with LC progression. Moreover, TGF-β is involved in promoting invasiveness and metastasis, via epithelial to mesenchymal transition (EMT) induction, where TGF-β is the major driver. Thus, a TGF-β-EMT signature may be considered a potential predictive marker in LC prognosis, and TGF-β-EMT inhibition has been demonstrated to prevent metastasis in various animal models. Concerning a LC therapeutic approach, some TGF-β and TGF-β-EMT inhibitors could be used in combination with chemo- and immunotherapy without major side effects, thereby improving cancer therapy. Overall, targeting TGF-β may be a valid possibility to fight LC, both in improving LC prognosis and cancer therapy, via a novel approach that could open up new effective strategies against this aggressive cancer. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumour thought to arise from ductal cells via pancreatic intraepithelial neoplasia (PanIN) precursor lesions. Modelling of different genetic events in mice suggests both ductal and acinar cells can give rise to PDAC. However, the impact of cellular context alone on tumour development and phenotype is unknown. DESIGN: We examined the contribution of cellular origin to PDAC development by inducing PDAC-associated mutations, KrasG12D expression and Trp53 loss, specifically in ductal cells (Sox9CreER;KrasLSL-G12D;Trp53flox/flox (Duct:KPcKO )) or acinar cells (Ptf1aCreER;KrasLSL-G12D;Trp53flox/flox (Acinar:KPcKO )) in mice. We then performed a thorough analysis of the resulting histopathological changes. RESULTS: Both mouse models developed PDAC, but Duct:KPcKO mice developed PDAC earlier than Acinar:KPcKO mice. Tumour development was more rapid and associated with high-grade murine PanIN (mPanIN) lesions in Duct:KPcKO mice. In contrast, Acinar:KPcKO mice exhibited widespread metaplasia and low-grade as well as high-grade mPanINs with delayed progression to PDAC. Acinar-cell-derived tumours also had a higher prevalence of mucinous glandular features reminiscent of early mPanIN lesions. CONCLUSION: These findings indicate that ductal cells are primed to form carcinoma in situ that become invasive PDAC in the presence of oncogenic Kras and Trp53 deletion, while acinar cells with the same mutations appear to require a prolonged period of transition or reprogramming to initiate PDAC. Our findings illustrate that PDAC can develop in multiple ways and the cellular context in which mutations are acquired has significant impact on precursor lesion initiation, disease progression and tumour phenotype.

Hepatocellular carcinoma (HCC), one of the most prevalent cancers, with a high mortality rate worldwide, seriously impairs patient health. The lack of accurate targets impedes the early screening and diagnosis of HCC and is associated with a poor response to routine therapies. Extracellular vesicles (EVs), comprising exosomes, microvesicles, and apoptotic bodies, are lipid bilayer membrane-derived nanometer-sized vesicles. EVs can be secreted from various cancer cells and release diverse biomolecules, such as DNA, RNA, proteins, metabolites, and lipids, making them a potential source of biomarkers and regulators of the tumor microenvironment. Emerging evidence suggests that EVs are involved in intercellular communication by carrying biological information. These EVs elicit physiological functions and are involved in the oncogenesis of HCC, such as proliferation, invasion, metastasis, and chemoresistance of HCC. EVs have also been considered promising biomarkers and nanotherapeutic targets for HCC. Therefore, this review sheds light on the current understanding of the interactions between EVs and HCC to propose potential biomarkers and nanotherapeutic strategies.

PurposeLacrimal gland benign lymphoepithelial lesion (LGBLEL) is an IgG4-related disease of unknown etiology with a risk for malignant transformation. Estrogen is considered to be related to LGBLEL onset.MethodsSeventy-eight LGBLEL and 13 control clinical samples were collected and studied to determine the relationship between estrogen and its receptors and LGBLEL development.ResultsThe serological analysis revealed no significant differences in the levels of three estrogens be-tween the LGBLEL and control groups. However, immunohistochemical analyses indicated that the expression levels of ERβ and its downstream receptor RERG were relatively lower in LGBLEL samples than in control samples, with higher expression in the lacrimal gland and lower expression in the lymphocyte infiltration region. However, low expression of ERα was detected. The transcriptome sequence analysis revealed upregulated genes associated with LGBLEL enriched in lymphocyte proliferation and activation function; downregulated genes were enriched in epithelial and vascular proliferation functions. The key genes and gene networks were further analyzed. Interactions between B cells and epithelial cells were analyzed due to the identified involvement of leukocyte subsets and epithelial cells. B cell proliferation was found to potentially contribute to lacrimal gland apoptosis.ConclusionTherefore, the tissue-heterogeneous expression pattern of ERβ is potentially related to the clinical manifestations and progression of LGBLEL, although further investigations are required to confirm this finding.

Simple Summary: Connexins are proteins which comprise gap junctions in cells. These junctions can directly connect neighboring cells and the cell interior with the extracellular microenvironment and thus they act as tissue integrators. Alterations in connexin regulation can lead to unfavorable shifts in the tissue adhesive context thus eradicating the constraints of the normal tissue microenvironment, triggering (or enhancing) cell motility. This review tries to examine the role of connexins in orchestrating the tumor microenvironment and hence their role in malignancy. Today's research on the processes of carcinogenesis and the vital activity of tumor tissues implies more attention be paid to constituents of the tumor microenvironment and their interactions. These interactions between cells in the tumor microenvironment can be mediated via different types of protein junctions. Connexins are one of the major contributors to intercellular communication. They form the gap junctions responsible for the transfer of ions, metabolites, peptides, miRNA, etc., between neighboring tumor cells as well as between tumor and stromal cells. Connexin hemichannels mediate purinergic signaling and bidirectional molecular transport with the extracellular environment. Additionally, connexins have been reported to localize in tumor-derived exosomes and facilitate the release of their cargo. A large body of evidence implies that the role of connexins in cancer is multifaceted. The pro- or anti-tumorigenic properties of connexins are determined by their abundance, localization, and functionality as well as their channel assembly and non-channel functions. In this review, we have summarized the data on the contribution of connexins to the formation of the tumor microenvironment and to cancer initiation and progression. [ABSTRACT FROM AUTHOR]

Chronic stress results in disturbances of body hormones through the neuroendocrine system. Cancer patients often experience recurrent anxiety and restlessness during disease progression and treatment, which aggravates disease progression and hinders treatment effects. Recent studies have shown that chronic stress-regulated neuroendocrine systems secret hormones to activate many signaling pathways related to tumor development in tumor cells. The activated neuroendocrine system acts not only on tumor cells but also modulates the survival and metabolic changes of surrounding non-cancerous cells. Current clinical evidences also suggest that chronic stress affects the outcome of cancer treatment. However, in clinic, there is lack of effective treatment for chronic stress in cancer patients. In this review, we discuss the main mechanisms by which chronic stress regulates the tumor microenvironment, including functional regulation of tumor cells by stress hormones (stem cell-like properties, metastasis, angiogenesis, DNA damage accumulation, and apoptotic resistance), metabolic reprogramming and immune escape, and peritumor neuromodulation. Based on the current clinical treatment framework for cancer and chronic stress, we also summarize pharmacological and non-pharmacological therapeutic approaches to provide some directions for cancer therapy. [ABSTRACT FROM AUTHOR]

Background A thorough analysis of clonal evolution commonly requires integration of diverse sources of data (e.g. karyotyping, next-generation sequencing, and clinical information). Subsequent to actual reconstruction of clonal evolution, detailed analysis and interpretation of the results are essential. Often, however, only few tumor samples per patient are available. Thus, information on clonal development and therapy effect may be incomplete. Furthermore, analysis of biallelic events—considered of high relevance with respect to disease course—can commonly only be realized by time-consuming analysis of the raw results and even raw sequencing data. Results We developed clevRvis, an R/Bioconductor package providing an extensive set of visualization techniques for clonal evolution. In addition to common approaches for visualization, clevRvis offers a unique option for allele-aware representation: plaice plots. Biallelic events may be visualized and inspected at a glance. Analyzing 4 public datasets, we show that plaice plots help to gain new insights into tumor development and investigate hypotheses on disease progression and therapy resistance. In addition to a graphical user interface, automatic phylogeny-aware color coding of the plots, and an approach to explore alternative trees, clevRvis provides 2 algorithms for fully automatic time point interpolation and therapy effect estimation. Analyzing 2 public datasets, we show that both approaches allow for valid approximation of a tumor's development in between measured time points. Conclusions clevRvis represents a novel option for user-friendly analysis of clonal evolution, contributing to gaining new insights into tumor development. [ABSTRACT FROM AUTHOR]

Different types of cytokines, growth factors, or hormones present within the tumor microenvironment that can activate the JAK-STAT signaling pathway by binding to their specific cell surface receptors. The constitutive activation of the JAK-STAT pathway can promote uncontrolled cell proliferation and prevent apoptosis contributing to tumor development. Activation of the JAK-STAT pathway is controlled by several regulatory molecules, particularly the suppressor of cytokine signaling (SOCS) family consisting of eight members, which include SOCS1-SOCS7 and the cytokine-inducible SH2-containing (CIS) proteins. In prostate cancer cells, the irregular expression of the SOCS1-SOCS3, SOCS5-SOCS7 as well as CIS can similarly and differentially result in the initiation of various cellular signaling pathways (in particular JAK-STAT3, MAPK, ERK) that promote cell proliferation, migration, invasion and viability; cell cycle progression; epithelial-mesenchymal transition; angiogenesis; resistance to therapy; immune evasion; and chronic inflammation within the tumor microenvironment which lead to tumor progression, metastasis and poor prognosis. Epigenetic modifications, mainly due to DNA methylation, microRNAs, pro-inflammatory cytokines, growth factors and androgens can influence the expression of the SOCS molecules in prostate cancer cells. Using strategies to modulate, restore or enhance the expression of SOCS proteins, may help overcome treatment resistance and improve the efficacy of existing therapies. In this review, we provide a comprehensive explanation regarding SOCS dysregulation in prostate cancer to provide insights into the mechanisms underlying the dysregulation of SOCS proteins. This knowledge may pave the way for the development of novel therapeutic strategies to manage prostate cancer by restoring and modulating the expression of SOCS molecules. [Display omitted] • DNA methylation, miRNAs, cytokines, and androgens affect SOCS expression. • Aberrant expression of SOCS1-SOCS3, SOCS5-SOCS7 and CIS occurs in prostate cancer. • Dysregulated SOCS expression promotes prostate cancer development and progression. • SOCS proteins mainly exert anti-tumorigenic effects in prostate cancer. • Restoring SOCS expression can be considered as a strategy to manage prostate cancer. [ABSTRACT FROM AUTHOR]

From previous studies of negatively correlating the expression of human METCAM/MUC18 with the pathology of nasopharyngeal carcinoma (NPC), we have suggested that human METCAM/MUC18 (huMETCAM/MUC18) might play a tumor suppressor role in the development of nasopharyngeal carcinoma. To scrutinize this hypothesis, we investigated the effects of huMETCAM/MUC18′s over-expression on in vitro cellular behavior and on the in vivo tumorigenesis of one NPC cell line (NPC-TW01). HuMETCAM/MUC18 cDNA was first transfected into the NPC-TW01 cell line, which was established from NPC type I, and many G418-resistant clones were obtained. Then, two NPC-TW01 clones, which expressed high and medium levels of huMETCAM/MUC18, respectively, and one empty vector (control) clone were used to test the effects of huMETCAM/MUC18′s over-expression on in vitro behaviors and on in vivo tumorigenesis (via subcutaneous injection) in athymic nude mice (Balb/cAnN.Cg-Foxnlnu/Cr1Nar1). The time course of tumor proliferation and the final tumor weights were determined. Tumor sections were used for the histology and immunohistochemistry (IHC) studies. Tumor lysates were used for determining the expression levels of huMETCAM/MUC18 and various downstream key effectors. HuMETCAM/MUC18′s over-expression reduced in vitro motility and invasiveness and altered growth behaviors in 3D basement membrane culture assays, and it decreased the in vivo tumorigenicity of the NPC-TW01 cells. The tumor cells from a high-expressing clone were clustered and confined in small areas, whereas those from a vector control clone were more spread out, suggesting that the tumor cells from the high-expressing clone appeared to stay dormant in micro-clusters. Expression levels of the proliferation index, an index of the metabolic switch to aerobic glycolysis, angiogenesis indexes, and survival pathway indexes were reduced, whereas the pro-apoptosis index increased in the corresponding tumors. The over-expression of huMETCAM/MUC18 in the NPC-TW01 cells decreased the epithelial-to-mesenchymal transition and the in vitro and in vitro tumorigenesis, suggesting that it plays a tumor suppressor role in the development of type I NPC, perhaps by increasing apoptosis and decreasing angiogenesis, proliferation, and the metabolic switch to aerobic glycolysis. [ABSTRACT FROM AUTHOR]

Nowadays, molecular and immunological research is essential for the better understanding of tumor cells pathophysiology. The increasing number of neoplasms has been taken under 'the molecular magnifying glass' and, therefore, it is possible to discover complex relationships between the cytophysiology and immune system action. An example could be renal cell carcinoma (RCC) which has deep interactions with immune mediators such as Interleukin 17 (IL-17)—an inflammatory cytokine reacting to tissue damage and external pathogens. RCC is one of the most fatal urological cancers because of its often late diagnosis and poor susceptibility to therapies. IL-17 and its relationship with tumors is extremely complex and constitutes a recent topic for numerous studies. What is worth highlighting is IL-17's dual character in cancer development—it could be pro- as well as anti-tumorigenic. The aim of this review is to summarize the newest data considering multiple connections between IL-17 and RCC. [ABSTRACT FROM AUTHOR]

Innate and adaptive immune cells monitor, recognize, and eliminate transformed cells. Innate lymphoid cells (ILCs) are innate counterparts of T cells that play a key role in many facets of the immune response and have a profound impact on disease states, including cancer. ILCs regulate immune responses by responding and integrating a wide range of signals within the local microenvironment. As primarily tissue-resident cells, ILCs are ideally suited to sense malignant transformation and initiate anti-tumor immunity. However, as ILCs have been associated with anti-tumor and pro-tumor activities in established tumors, they could potentially have dual functions during carcinogenesis by promoting or suppressing the malignant outgrowth of premalignant lesions. Here we discuss emerging evidence that shows that ILCs can impact early tumor development by regulating immune responses against transformed cells, as well as the environmental cues that potentially induce ILC activation in premalignant lesions. [ABSTRACT FROM AUTHOR]

Cancer-related deaths are very commonly attributed to complications from metastases to neighboring as well as distant organs. Dissociate response in the treatment of pancreatic adenocarcinoma is one of the main causes of low treatment success and low survival rates. This behavior could not be explained by transcriptomics or genomics; however, differences in the composition at the protein level could be observed. We have characterized the proteomic composition of primary pancreatic adenocarcinoma and distant metastasis directly in human tissue samples, utilizing mass spectrometry imaging. The mass spectrometry data was used to train and validate machine learning models that could distinguish both tissue entities with an accuracy above 90%. Model validation on samples from another collection yielded a correct classification of both entities. Tentative identification of the discriminative molecular features showed that collagen fragments (COL1A1, COL1A2, and COL3A1) play a fundamental role in tumor development. From the analysis of the receiver operating characteristic, we could further advance some potential targets, such as histone and histone variations, that could provide a better understanding of tumor development, and consequently, more effective treatments. [ABSTRACT FROM AUTHOR]

Abstract Aim This study aimed to explore the mechanism of LncRNA urothelial carcinoma-associated 1 (UCA1) promoting cisplatin resistance in lung adenocarcinoma (LUAD). Method The UCA1 expression level in LUAD cell lines was detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). We overexpressed UCA1 in A549 cells and downregulated UCA1 in A549/DDP cells by the lentivirus‑mediated technique. Subsequently, in vitro, and in vivo functional experiments were performed to investigate the functional roles of UCA1 in the growth and metastasis of LUAD cell lines. Furthermore, RNA pulldown, mass spectrometry, and RNA immunoprecipitation technique were performed to analyze various downstream target factors regulated by UCA1. Results The results revealed a higher UCA1 expression level in A549/DDP cells and LUAD tissues than in A549 cells and adjacent cancer tissues. UCA1 expression was significantly associated with distant metastasis, clinical stage, and survival time of patients with LUAD. UCA1 overexpression significantly increased the proliferation, invasion, clone formation, and cisplatin resistance ability and enhanced the expression levels of proliferating cell nuclear antigen and excision repair cross-complementing gene 1 in A549 cells. However, these trends were mostly reversed after the knockdown of UCA1 in A549/DDP cells. Tumorigenic assays in nude mice showed that UCA1 knockdown significantly inhibited tumor growth and reduced cisplatin resistance. Enolase 1 was the RNA-binding protein (RBP) of UCA1. Conclusion Based on the results, we concluded that UCA1 promoted LUAD progression and cisplatin resistance and hence could be a potential diagnostic marker and therapeutic target in patients with LUAD.

Abstract Malignant tumor has become one of the major diseases that seriously endangers human health. Numerous studies have demonstrated that tumor microenvironment (TME) is closely associated with patient prognosis. Tumor growth and progression are strongly dependent on its surrounding tumor microenvironment, because the optimal conditions originated from stromal elements are required for cancer cell proliferation, invasion, metastasis and drug resistance. The tumor microenvironment is an environment rich in immune/inflammatory cells and accompanied by a continuous, gradient of hypoxia and pH. Overcoming immunosuppressive environment and boosting anti-tumor immunity may be the key to the prevention and treatment of cancer. Most traditional Chinese medicine have been proved to have good anti-tumor activity, and they have the advantages of better therapeutic effect and few side effects in the treatment of malignant tumors. An increasing number of studies are giving evidence that alkaloids extracted from traditional Chinese medicine possess a significant anticancer efficiency via regulating a variety of tumor-related genes, pathways and other mechanisms. This paper reviews the anti-tumor effect of alkaloids targeting tumor microenvironment, and further reveals its anti-tumor mechanism through the effects of alkaloids on different components in tumor microenvironment.