A control engineering approach to understanding the TGF-β paradox in cancer

TGF-β, a key cytokine that regulates diverse cellular processes, including proliferation and apoptosis, appears to function paradoxically as a tumour suppressor in normal cells, and as a tumour promoter in cancer cells, but the mechanisms underlying such contradictory roles remain unknown. In particular, given that this cytokine is primarily a tumour suppressor, the conundrum of the unusually high level of TGF-β observed in the primary cancer tissue and blood samples of cancer patients with the worst prognosis, remains unresolved. To provide a quantitative explanation of these paradoxical observations, we present, from a control theory perspective, a mechanistic model of TGF-β-driven regulation of cell homeostasis. Analysis of the overall system model yields quantitative insight into how cell population is regulated, enabling us to propose a plausible explanation for the paradox: with the tumour suppressor role of TGF-β unchanged from normal to cancer cells, we demonstrate that the observed increased level of TGF-β is an effect of cancer cell phenotypic progression (specifically, acquired TGF-β resistance), not the cause . We are thus able to explain precisely why the clinically observed correlation between elevated TGF-β levels and poor prognosis is in fact consistent with TGF-β's original (and unchanged) role as a tumour suppressor.

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The role of hypoxia in endometrial cancer

Current Pharmaceutical Biotechnology ◽

10.2174/1389201022666210224130022 ◽

2021 ◽

Vol 22 ◽

Author(s):

Yarely M. Salinas-Vera ◽

Dolores Gallardo-Rincón ◽

Erika Ruíz-García ◽

Macrina B. Silva-Cázares ◽

Carmen Sol de la Peña-Cruz ◽

...

Keyword(s):

Endometrial Cancer ◽

Cell Survival ◽

Cancer Cells ◽

Cancer Cell ◽

Targeted Therapies ◽

Current Knowledge ◽

Vasculogenic Mimicry ◽

Cellular Processes ◽

Corpus Uteri

: Endometrial cancer represents the most frequent neoplasia from the corpus uteri, and comprises the 14th leading cause of death in women worldwide. Risk factors that contribute to the disease include early menarche, late menopause, nulliparity, and menopausal hormone use, as well as hypertension and obesity comorbidities. The clinical effectiveness of chemotherapy is variable, suggesting that novel molecular targeted therapies against specific cellular processes associated with the maintenance of cancer cell survival and therapy resistance urged to ameliorate the rates of success in endometrial cancer treatment. In the course of tumor growth, cancer cells must adapt to decreased oxygen availability in the microenvironment by upregulation of hypoxia-inducible factors, which orchestrate the activation of a transcriptional program leading to cell survival. During this adaptative process, the hypoxic cancer cells may acquire invasive and metastatic properties as well as increased cell proliferation and resistance to chemotherapy, enhanced angiogenesis, vasculogenic mimicry, and maintenance of cancer cell stemness, which contribute to more aggressive cancer phenotypes. Several studies have shown that hypoxia-inducible factor 1 alpha (HIF-1α) protein is aberrantly overexpressed in many solid tumors from breast, prostate, ovarian, bladder, colon, brain, and pancreas. Thus, it has been considered an important therapeutic target. Here, we reviewed the current knowledge of the relevant roles of cellular hypoxia mechanisms and HIF-1α functions in diverse processes associated with endometrial cancer progression. In addition, we also summarize the role of microRNAs in the posttranscriptional regulation of protein-encoding genes involved in the hypoxia response in endometrial cancer. Finally, we pointed out the need for urgent targeted therapies to impair the cellular processes activated by hypoxia in the tumor microenvironment.

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Role of Glutathione in Cancer Progression and Chemoresistance

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/972913 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 423

Author(s):

Nicola Traverso ◽

Roberta Ricciarelli ◽

Mariapaola Nitti ◽

Barbara Marengo ◽

Anna Lisa Furfaro ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Differentiation ◽

Cancer Progression ◽

Anticancer Agents ◽

Cytotoxic Effects ◽

Cellular Processes ◽

Proliferation And Apoptosis ◽

Glutathione Disulphide ◽

Increased Susceptibility

Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and disturbances in GSH homeostasis are involved in the etiology and progression of many human diseases including cancer. While GSH deficiency, or a decrease in the GSH/glutathione disulphide (GSSG) ratio, leads to an increased susceptibility to oxidative stress implicated in the progression of cancer, elevated GSH levels increase the antioxidant capacity and the resistance to oxidative stress as observed in many cancer cells. The present review highlights the role of GSH and related cytoprotective effects in the susceptibility to carcinogenesis and in the sensitivity of tumors to the cytotoxic effects of anticancer agents.

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Advances in the role of m6A RNA modification in cancer metabolic reprogramming

Cell & Bioscience ◽

10.1186/s13578-020-00479-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Xiu Han ◽

Lin Wang ◽

Qingzhen Han

Keyword(s):

Cancer Cells ◽

Epigenetic Modification ◽

Metabolic Reprogramming ◽

Regulatory Mechanisms ◽

Rna Modification ◽

Biological Functions ◽

Rna Transcription ◽

Cellular Processes ◽

Metabolic Genes

Abstract N6-methyladenosine (m6A) modification is the most common internal modification of eukaryotic mRNA and is widely involved in many cellular processes, such as RNA transcription, splicing, nuclear transport, degradation, and translation. m6A has been shown to plays important roles in the initiation and progression of various cancers. The altered metabolic programming of cancer cells promotes their cell-autonomous proliferation and survival, leading to an indispensable hallmark of cancers. Accumulating evidence has demonstrated that this epigenetic modification exerts extensive effects on the cancer metabolic network by either directly regulating the expression of metabolic genes or modulating metabolism-associated signaling pathways. In this review, we summarized the regulatory mechanisms and biological functions of m6A and its role in cancer metabolic reprogramming.

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The Role of Tumor-Associated Macrophages in the Progression and Chemoresistance of Ovarian Cancer

Cells ◽

10.3390/cells9051299 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1299 ◽

Cited By ~ 2

Author(s):

Marek Nowak ◽

Magdalena Klink

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Immune Cells ◽

Ovarian Cancer Cells ◽

High Plasticity ◽

Tumor Associated Macrophages ◽

Survival Signaling ◽

High Level ◽

Stimulating Factor

Tumor-associated macrophages (TAMs) constitute the main population of immune cells present in the ovarian tumor microenvironment. These cells are characterized by high plasticity and can be easily polarized by colony-stimulating factor-1, which is released by tumor cells, into an immunosuppressive M2-like phenotype. These cells are strongly implicated in both the progression and chemoresistance of ovarian cancer. The main pro-tumoral function of M2-like TAMs is the secretion of a variety of cytokines, chemokines, enzymes and exosomes that reach microRNAs, directly inducing the invasion potential and chemoresistance of ovarian cancer cells by triggering their pro-survival signaling pathways. The M2-like TAMs are also important players in the metastasis of ovarian cancer cells in the peritoneum through their assistance in spheroid formation and attachment of cancer cells to the metastatic area—the omentum. Moreover, TAMs interplay with other immune cells, such as lymphocytes, natural killer cells, and dendritic cells, to inhibit their responsiveness, resulting in the development of immunosuppression. The detrimental character of the M2-like type of TAMs in ovarian tumors has been confirmed by a number of studies, demonstrating the positive correlation between their high level in tumors and low overall survival of patients.

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Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer

BMC Cancer ◽

10.1186/s12885-019-6333-6 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Xueqing Sun ◽

Qing Qu ◽

Yimin Lao ◽

Mi Zhang ◽

Xiaoling Yin ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Suppressor ◽

Cancer Cells ◽

Cell Line ◽

Cancer Tissue ◽

Cancer Associated Fibroblasts ◽

Autocrine Signaling ◽

Stromal Fibroblasts ◽

Signal Transducers

Abstracts Background Interleukin-6 (IL-6) is commonly highly secreted in the breast cancer (BrCA) microenvironment and implicated in disease development. In this study, we aimed to determine the role of the IL-6/pSTAT3/HIC1 axis in the breast cancer microenvironment, including in cancer-associated fibroblasts (CAFs) and breast cancer cells. Methods Stromal fibroblasts from the breast cancer tissue were isolated, and the supernatants of the fibroblasts were analyzed. Recombinant human IL-6 (rhIL-6) was applied to simulate the effect of CAF-derived IL-6 to study the mechanism of HIC1 (tumor suppressor hypermethylated in cancer 1) downregulation. IL-6 was knocked down in the high IL-6-expressing BrCA cell line MDA-MB-231, which enabled the investigation of the IL-6/pSTAT3/HIC1 axis in the autocrine pathway. Results Increased IL-6 was found in the supernatant of isolated CAFs, which suppressed HIC1 expression in cancer cells and promoted BrCA cell proliferation. After stimulating the BrCA cell line SK-BR-3 (where IL-6R is highly expressed) with rhIL-6, signal transducers and activators of transcription 3 (STAT3) was found to be phosphorylated and HIC1 decreased, and a STAT3 inhibitor completely rescued HIC1 expression. Moreover, HIC1 was restored upon knocking down IL-6 expression in MDA-MB-231 cells, accompanied by a decrease in STAT3 activity. Conclusions These findings indicate that IL-6 downregulates the tumor suppressor HIC1 and promotes BrCA development in the tumor microenvironment through paracrine or autocrine signaling.

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Emerging impact of the long noncoding RNA MIR22HG on proliferation and apoptosis in multiple human cancers

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01784-8 ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Le Zhang ◽

Cuixia Li ◽

Xiulan Su

Keyword(s):

Chromatin Remodeling ◽

Noncoding Rna ◽

Potential Role ◽

Immune Escape ◽

Prognostic Biomarker ◽

Cellular Processes ◽

Proliferation And Apoptosis ◽

Underlying Mechanisms ◽

Competitive Endogenous Rna

AbstractAn increasing number of studies have shown that long noncoding RNAs (lncRNAs) play important roles in diverse cellular processes, including proliferation, apoptosis, migration, invasion, chromatin remodeling, metabolism and immune escape. Clinically, the expression of MIR22HG is increased in many human tumors (colorectal cancer, gastric cancer, hepatocellular carcinoma, lung cancer, and thyroid carcinoma), while in others (esophageal adenocarcinoma and glioblastoma), it is significantly decreased. Moreover, MIR22HG has been reported to function as a competitive endogenous RNA (ceRNA), be involved in signaling pathways, interact with proteins and interplay with miRNAs as a host gene to participate in tumorigenesis and tumor progression. In this review, we describe the biological functions of MIR22HG, reveal its underlying mechanisms for cancer regulation, and highlight the potential role of MIR22HG as a novel cancer prognostic biomarker and therapeutic target that can increase the efficacy of immunotherapy and targeted therapy for cancer treatment.

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Role of proliferation and apoptosis in net growth rates of human breast cancer cells (MCF-7) treated with oestradiol and/or tamoxifen

Cell Proliferation ◽

10.1046/j.1365-2184.1999.3250289.x ◽

1999 ◽

Vol 32 (5) ◽

pp. 289-302 ◽

Cited By ~ 26

Author(s):

P. E. Budtz

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Growth Rates ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Proliferation And Apoptosis ◽

Mcf 7

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ITPR3 Facilitates Tumor Growth, Metastasis and Stemness by Inducing the NF-ĸB/CD44 Pathway in Urinary Bladder Carcinoma

10.21203/rs.3.rs-135606/v1 ◽

2020 ◽

Author(s):

Mengzhao Zhang ◽

Lu Wang ◽

Yangyang Yue ◽

Lu Zhang ◽

Tianjie Liu ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Bladder Carcinoma ◽

Cancer Metastasis ◽

Critical Role ◽

Cancer Tissue ◽

Urinary Bladder Carcinoma ◽

Mesenchymal Transition ◽

Bladder Cancer Cells

Abstract Background: Bladder carcinoma is one of the most common urological cancers. ITPR3, as a ubiquitous endoplasmic reticulum calcium channel protein, was reported to be involved in the development and progression of various types of cancer. However, the potential roles and molecular mechanism of ITPR3 in bladder cancer are still unclear. Herein, we elucidated a novel role of ITPR3 in regulating the proliferation, metastasis, and stemness of bladder cancer cells.Methods: The expression of ITPR3 in bladder cancer was analyzed using public databases and bladder cancer tissue microarrays. To demonstrate the role of ITPR3 in regulating the NF-ĸB/CD44 pathway and the progression of bladder cancer, a series of molecular biology and biochemistry methods was performed on clinical tissues, along with in vivo and in vitro experiments. The methods used included western blot assay, quantitative RT-PCR assay, immunofluorescence assay, immunohistochemistry (IHC) assays, wound healing assay, Transwell assay, colony formation assay, tumorsphere formation assay, cell flow cytometry analysis, EdU assay, MTT assay, cell transfection, bisulfite sequencing PCR (BSP), a xenograft tumor model and a tail vein cancer metastasis model.Results: Higher ITPR3 expression was found in bladder cancer tissues and bladder cancer cells compared with the corresponding normal peritumor tissues and SV-HUC-1 cells, which was attributed to demethylation in the ITPR3 promoter region. ITPR3 promoted the proliferation of bladder cancer by accelerating cell cycle transformation and promoted local invasion and distant metastasis by inducing epithelial-to-mesenchymal transition (EMT). Meanwhile, ITPR3 maintained the cancer stemness phenotype by regulating CD44 expression. NF-κB, which is upstream of CD44, also played a critical role in this process.Conclusions: Our study clarifies that ITPR3 serves as an oncogene in bladder cancer cells and represents a novel candidate for bladder cancer diagnosis and treatment.

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