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Using MKK4’s metastasis suppressor function to identify and dissect cancer cell–microenvironment interactions during metastatic colonization

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Abstract

Host tissue microenvironment plays key roles in cancer progression and colonization of secondary organs. One example is ovarian cancer, which colonizes the peritoneal cavity and especially the omentum. Our research indicates that the interaction of ovarian cancer cells with the omental microenvironment can activate a stress-kinase pathway involving the mitogen-activated protein kinase kinase 4 (MKK4). A combination of clinical correlative and functional data suggests that MKK4 activation suppresses growth of ovarian cancer cells lodged in omentum. These findings prompted us to turn our focus to the cellular composition of the omental microenvironment and its role in regulating cancer growth. In this review, in addition to providing an overview of MKK4 function, we highlight a use for metastasis suppressors as a molecular tool to study cancer cell interaction with its microenvironment. We review features of the omentum that makes it a favorable microenvironment for metastatic colonization. In conclusion, a broader, evolutionary biology perspective is presented which we believe needs to be considered when studying the evolution of cancer cells within a defined microenvironment. Taken together, this approach can direct new multi-dimensional lines of research aimed at a mechanistic understanding of host tissue microenvironment, which could be used to realize novel targets for future research.

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Acknowledgments

Financial support was provided by the Pardee Foundation (J.T.V., C.W.R-S.), NCI/NIH 2RO1CA089569 (J.T.V., N.S., V.K., R.C., C.W.R-S.), DOD W81XWH-09-1-0127 (R.C., V.K., C.W.R-S.), Lederer Fund (J.T.V.), Section of Urology Research Funds (C.W. R-S, J.T.V.), NIH Grant T32 GM007197 (R. B.), and Graduate Training in Growth and Development T32 HD07009 (J.T.V.).

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Correspondence to Carrie Rinker-Schaeffer.

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Venkatesh Krishnan and Nathan Stadick contributed equally.

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Krishnan, V., Stadick, N., Clark, R. et al. Using MKK4’s metastasis suppressor function to identify and dissect cancer cell–microenvironment interactions during metastatic colonization. Cancer Metastasis Rev 31, 605–613 (2012). https://doi.org/10.1007/s10555-012-9371-y

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