Acquisition of Chemoresistance and EMT Phenotype Is Linked with Activation of the Endothelin A Receptor Pathway in Ovarian Carcinoma Cells

Rosanò, Laura; Cianfrocca, Roberta; Spinella, Francesca; Castro, Valeriana Di; Nicotra, Maria Rita; Lucidi, Alessandro; Ferrandina, Gabriella; Natali, Pier Giorgio; Bagnato, Anna

doi:10.1158/1078-0432.ccr-10-2325

Cited by 170 publications

(163 citation statements)

References 46 publications

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“…At the same time, the reduction of migratory Th17 from intestine in the cisplatin group may also explain the reduced Th17 frequency in that group. Meanwhile, cisplatin is known to induce cancer stem cells or stem cell-like phenotype (44,45). These cancer stem cells secrete large quantities of various proinflammatory mediators, including IL-17 (46), providing a possible explanation for the slightly increased (not significant) IL-17 in the cisplatin group.…”

Section: Discussionmentioning

confidence: 99%

Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice

Sung

Lee

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

486

386

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The beneficial roles of probiotics in lowering the gastrointestinal inflammation and preventing colorectal cancer have been frequently demonstrated, but their immunomodulatory effects and mechanism in suppressing the growth of extraintestinal tumors remain unexplored. Here, we adopted a mouse model and metagenome sequencing to investigate the efficacy of probiotic feeding in controlling s.c. hepatocellular carcinoma (HCC) and the underlying mechanism suppressing the tumor progression. Our result demonstrated that Prohep, a novel probiotic mixture, slows down the tumor growth significantly and reduces the tumor size and weight by 40% compared with the control. From a mechanistic point of view the down-regulated IL-17 cytokine and its major producer Th17 cells, whose levels decreased drastically, played critical roles in tumor reduction upon probiotics feeding. Cell staining illustrated that the reduced Th17 cells in the tumor of the probiotictreated group is mainly caused by the reduced frequency of migratory Th17 cells from the intestine and peripheral blood. In addition, shotgun-metagenome sequencing revealed the crosstalk between gut microbial metabolites and the HCC development. Probiotics shifted the gut microbial community toward certain beneficial bacteria, including Prevotella and Oscillibacter, that are known producers of antiinflammatory metabolites, which subsequently reduced the Th17 polarization and promoted the differentiation of antiinflammatory Treg/Tr1 cells in the gut. Overall, our study offers novel insights into the mechanism by which probiotic treatment modulates the microbiota and influences the regulation of the T-cell differentiation in the gut, which in turn alters the level of the proinflammatory cytokines in the extraintestinal tumor microenvironment.H epatocellular carcinoma (HCC) is one of the most common cancers, the sixth most common neoplasm, and the second most deadly type of cancer worldwide (1). The traditional HCC treatment, including surgical treatment, local ablation therapy, and chemotherapy, could offer potential cure, yet patients are facing many limitations including the poor hepatic reserve. HCC is clearly a disease for which alternative therapeutic strategies must be developed. A better understanding of the interactions between cancer cells and stromal components in the tumorassociated proinflammatory microenvironment would be important for the management of this disease.The tumor microenvironment is infiltrated with various immune cells such as T cells, macrophages, neutrophils, natural killer (NK) cells, and myeloid-derived suppressor cells. Inflammation is known to play a pivotal role in tumor development by escalating tumor angiogenesis and cell growth. Once a solid tumor is formed, inflammation arises in the tumor-promoting direction. At the same time, new vasculature is needed in the tumor to provide nutrients and oxygen to support the growth of cancer cells, and this process plays a critical role in HCC, a highly vascularized tumor (2). Inflammation and angiogene...

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Section: Discussionmentioning

confidence: 99%

Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice

Sung

Lee

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

486

386

View full text Add to dashboard Cite

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“…Nevertheless, antagonists of ET receptors, like atrasentan and zibotentan (ZD4054), used alone have also gained considerable interest in human clinical trials on the basis of their potential anticancer activity [43] . For instance, the ET A R blockade with the specific ET A R antagonist zibotentan restored drug sensitivity to cytotoxic-induced apoptosis and inhibited ovarian cancer cell invasion [44] .…”

Section: Gpcrs Activated By Peptidesmentioning

confidence: 99%

GPCRs and cancer

Lappano

2012

Acta Pharmacol Sin

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G-protein-coupled receptors (GPCRs), which represent the largest gene family in the human genome, play a crucial role in multiple physiological functions as well as in tumor growth and metastasis. For instance, various molecules like hormones, lipids, peptides and neurotransmitters exert their biological effects by binding to these seven-transmembrane receptors coupled to heterotrimeric G-proteins, which are highly specialized transducers able to modulate diverse signaling pathways. Furthermore, numerous responses mediated by GPCRs are not dependent on a single biochemical route, but result from the integration of an intricate network of transduction cascades involved in many physiological activities and tumor development. This review highlights the emerging information on the various responses mediated by a selected choice of GPCRs and the molecular mechanisms by which these receptors exert a primary action in cancer progression. These findings provide a broad overview on the biological activity elicited by GPCRs in tumor cells and contribute to the identification of novel pharmacological approaches for cancer patients.

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“…In addition, epithelial biomarkers (including E-cadherin) are lost, while mesenchymal markers (such as N-cadherin, vimentin and Snail) are acquired (11). EMT in cancer cells has been identified to facilitate metastasis and chemoresistance (12). Furthermore, an EMT phenomenon has been identified in a number of cancer cells, including cisplatin-resistant non-small-cell lung cancer (13), doxorubicin-resistant breast cancer (14) and sorafenib-resistant hepatocellular carcinoma cells (15).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, an EMT phenomenon has been identified in a number of cancer cells, including cisplatin-resistant non-small-cell lung cancer (13), doxorubicin-resistant breast cancer (14) and sorafenib-resistant hepatocellular carcinoma cells (15). Preventing EMT-associated signaling pathways plays an important role in inhibiting cancer cell migration and invasion, as well as reducing drug resistance (12). The occurrence of the EMT is associated with complex signaling pathways, including the Wnt, PI3K, Hedgehog, transforming growth factor-β (TGF-β) and Notch pathways (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Acquisition of 5-fluorouracil resistance induces epithelial-mesenchymal transitions through the Hedgehog signaling pathway in HCT-8 colon cancer cells

Liu

Zhao

et al. 2015

Oncology Letters

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Abstract. Colon cancer has a high incidence in individuals >60-years-old. The commonly used chemotherapeutic agent, 5-fluorouracil (5-FU), has gradually lost its potency in treating colorectal cancer following the acquisition of resistance. Drug resistance is usually associated with epithelial-mesenchymal transitions (EMTs) in cancer cells. In the present study, the EMT phenotypes of two colon cancer cell lines, wild-type (HCT-8/WT) and 5-FU-resistant (HCT-8/5-FU), were characterized following the analysis of cellular migration, proliferation, morphology and molecular changes. In order to further clarify the mechanism of EMT in HCT-8/5-FU cells, the effect of EMT pathway inhibitors upon drug sensitivity was investigated. The results revealed that the Hedgehog signaling pathway inhibitor, GDC0449, reversed drug resistance. Therefore, inhibition of the Hedgehog pathway may provide a novel chemotherapeutic strategy for the treatment of patients with 5-FU-resistant colon cancer.

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Acquisition of Chemoresistance and EMT Phenotype Is Linked with Activation of the Endothelin A Receptor Pathway in Ovarian Carcinoma Cells

Cited by 170 publications

References 46 publications

Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice

Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice

GPCRs and cancer

Acquisition of 5-fluorouracil resistance induces epithelial-mesenchymal transitions through the Hedgehog signaling pathway in HCT-8 colon cancer cells

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