Dataset Information

TRPV4 Regulates Breast Cancer Cell Extravasation, Stiffness and Actin Cortex.

ABSTRACT: Metastasis is a significant health issue. The standard mode of care is combination of chemotherapy and targeted therapeutics but the 5-year survival rate remains low. New/better drug targets that can improve outcomes of patients with metastatic disease are needed. Metastasis is a complex process, with each step conferred by a set of genetic aberrations. Mapping the molecular changes associated with metastasis improves our understanding of the etiology of this disease and contributes to the pipeline of targeted therapeutics. Here, phosphoproteomics of a xenograft-derived in vitro model comprising 4 isogenic cell lines with increasing metastatic potential implicated Transient Receptor Potential Vanilloid subtype 4 in breast cancer metastasis. TRPV4 mRNA levels in breast, gastric and ovarian cancers correlated with poor clinical outcomes, suggesting a wide role of TRPV4 in human epithelial cancers. TRPV4 was shown to be required for breast cancer cell invasion and transendothelial migration but not growth/proliferation. Knockdown of Trpv4 significantly reduced the number of metastatic nodules in mouse xenografts leaving the size unaffected. Overexpression of TRPV4 promoted breast cancer cell softness, blebbing, and actin reorganization. The findings provide new insights into the role of TRPV4 in cancer extravasation putatively by reducing cell rigidity through controlling the cytoskeleton at the cell cortex.

SUBMITTER: Lee WH

PROVIDER: S-EPMC4904279 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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TRPV4 Regulates Breast Cancer Cell Extravasation, Stiffness and Actin Cortex.

Lee Wen Hsin WH Choong Lee Yee LY Mon Naing Naing NN Lu SsuYi S Lin Qingsong Q Pang Brendan B Yan Benedict B Krishna Vedula Sri Ram VS Singh Himanshu H Tan Tuan Zea TZ Thiery Jean Paul JP Lim Chwee Teck CT Tan Patrick Boon Ooi PB Johansson Martin M Harteneck Christian C Lim Yoon Pin YP

Scientific reports 20160613

Metastasis is a significant health issue. The standard mode of care is combination of chemotherapy and targeted therapeutics but the 5-year survival rate remains low. New/better drug targets that can improve outcomes of patients with metastatic disease are needed. Metastasis is a complex process, with each step conferred by a set of genetic aberrations. Mapping the molecular changes associated with metastasis improves our understanding of the etiology of this disease and contributes to the pipel ...[more]

PMID: 27291497

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Project description:Changes in intracellular calcium [Ca(2+)](i) levels control critical cytosolic and nuclear events that are involved in the initiation and progression of tumor angiogenesis in endothelial cells (ECs). Therefore, the mechanism(s) involved in agonist-induced Ca(2+)(i) signaling is a potentially important molecular target for controlling angiogenesis and tumor growth. Several studies have shown that blood vessels in tumors differ from normal vessels in their morphology, blood flow and permeability. We had previously reported a key role for arachidonic acid (AA)-mediated Ca(2+) entry in the initial stages of tumor angiogenesis in vitro. In this study we assessed the mechanism involved in AA-induced EC migration. We report that TRPV4, an AA-activated channel, is differentially expressed in EC derived from human breast carcinomas (BTEC) as compared with 'normal' EC (HMVEC). BTEC display a significant increase in TRPV4 expression, which was correlated with greater Ca(2+) entry, induced by AA or 4?PDD (a selective TRPV4 agonist) in the tumor-derived ECs. Wound-healing assays revealed a key role of TRPV4 in regulating cell migration of BTEC but not HMVEC. Knockdown of TRPV4 expression completely abolished AA-induced BTEC migration, suggesting that TRPV4 mediates the pro-angiogenic effects promoted by AA. Furthermore, pre-incubation of BTEC with AA induced actin remodeling and a subsequent increase in the surface expression of TRPV4. This was consistent with the increased plasma membrane localization of TRPV4 and higher AA-stimulated Ca(2+) entry in the migrating cells. Together, the data presented herein demonstrate that: (1) TRPV4 is differentially expressed in tumor-derived versus 'normal' EC; (2) TRPV4 has a critical role in the migration of tumor-derived but not 'normal' EC migration; and (3) AA induces actin remodeling in BTEC, resulting in a corresponding increase of TRPV4 expression in the plasma membrane. We suggest that the latter is critical for migration of EC and thus in promoting angiogenesis and tumor growth.

Dataset Information

TRPV4 Regulates Breast Cancer Cell Extravasation, Stiffness and Actin Cortex.

Publications

TRPV4 Regulates Breast Cancer Cell Extravasation, Stiffness and Actin Cortex.

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