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Extracellular matrix as a contextual determinant of transforming growth factor-? signaling in epithelial-mesenchymal transition and in cancer.

ABSTRACT: Extracellular matrix (ECM) provides both structural support and contextual information to cells within tissues and organs. The combination of biochemical and biomechanical signals from the ECM modulates responses to extracellular signals toward differentiation, proliferation, or apoptosis; alterations in the ECM are necessary for development and remodeling processes, but aberrations in the composition and organization of ECM are associated with disease pathology and can predispose to development of cancer. The primary cell surface sensors of the ECM are the integrins, which provide the physical connection between the ECM and the cytoskeleton and also convey biochemical information about the composition of the ECM. Transforming growth factor-? (TGF-?) is an extracellular signaling molecule that is a powerful controller of a variety of cellular functions, and that has been found to induce very different outcomes according to cell type and cellular context. It is becoming clear that ECM-mediated signaling through integrins is reciprocally influenced by TGF-?: integrin expression, activation, and responses are affected by cellular exposure to TGF-?, and TGF-? activation and cellular responses are in turn controlled by signaling from the ECM through integrins. Epithelial-mesenchymal transition (EMT), a physiological process that is activated by TGF-? in normal development and in cancer, is also affected by the composition and structure of the ECM. Here, we will outline how signaling from the ECM controls the contextual response to TGF-?, and how this response is selectively modulated during disease, with an emphasis on recent findings, current challenges, and future opportunities.

SUBMITTER: Cichon MA

PROVIDER: S-EPMC4594483 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Extracellular matrix as a contextual determinant of transforming growth factor-β signaling in epithelial-mesenchymal transition and in cancer.

Cichon Magdalena A MA Radisky Derek C DC

Cell adhesion & migration 20140101 6

Extracellular matrix (ECM) provides both structural support and contextual information to cells within tissues and organs. The combination of biochemical and biomechanical signals from the ECM modulates responses to extracellular signals toward differentiation, proliferation, or apoptosis; alterations in the ECM are necessary for development and remodeling processes, but aberrations in the composition and organization of ECM are associated with disease pathology and can predispose to development ...[more]

PMID: 25482625

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Project description:Transforming growth factor-? (TGF-?) and epidermal growth factor (EGF) have critical roles in regulating the metastasis of aggressive breast cancers, yet the impact of epithelial-mesenchymal transition (EMT) induced by TGF-? in altering the response of breast cancer cells to EGF remains unknown. We show in this study that murine metastatic 4T1 breast cancer cells formed compact and dense spheroids when cultured under three-dimensional (3D) conditions, which was in sharp contrast to the branching phenotypes exhibited by their nonmetastatic counterparts. Using the human MCF10A series, we show that epithelial-type and nonmetastatic breast cancer cells were unable to invade to EGF, whereas their mesenchymal-type and metastatic counterparts readily invaded to EGF. Furthermore, EMT induced by TGF-? was sufficient to manifest dense spheroid morphologies, a phenotype that increased primary tumor exit and invasion to EGF. Post-EMT invasion to EGF was dependent on increased activation of EGF receptor (EGFR) and p38 mitogen-activated protein kinase, all of which could be abrogated either by pharmacologic (PF-562271) or by genetic (shRNA) targeting of focal adhesion kinase (FAK). Mechanistically, EMT induced by TGF-? increased cell-surface levels of EGFR and prevented its physical interaction with E-cadherin, leading instead to the formation of oncogenic signaling complexes with T?R-II. Elevated EGFR expression was sufficient to transform normal mammary epithelial cells, and to progress their 3D morphology from that of hollow acini to branched structures characteristic of nonmetastatic breast cancer cells. Importantly, we show that TGF-? stimulation of EMT enabled this EGFR-driven breast cancer model to abandon their inherent branching architecture and form large, undifferentiated masses that were hyperinvasive to EGF and showed increased pulmonary tumor growth upon tail vein injection. Finally, chemotherapeutic targeting of FAK was sufficient to revert the aggressive behaviors of these structures. Collectively, this investigation has identified a novel EMT-based approach to neutralize the oncogenic activities of EGF and TGF-? in aggressive and invasive forms of breast cancer.

Dataset Information

Extracellular matrix as a contextual determinant of transforming growth factor-? signaling in epithelial-mesenchymal transition and in cancer.

Publications

Extracellular matrix as a contextual determinant of transforming growth factor-β signaling in epithelial-mesenchymal transition and in cancer.

Similar Datasets

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