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McLane JS, Ligon LA. Stiffened Extracellular Matrix and Signaling from Stromal Fibroblasts via Osteoprotegerin Regulate Tumor Cell Invasion in a 3-D Tumor in Situ Model. Cancer Microenviron. 2016;9(2):127-139doi: 10.1007/s12307-016-0188-z.
McLane, J. S., & Ligon, L. A. (2016). Stiffened Extracellular Matrix and Signaling from Stromal Fibroblasts via Osteoprotegerin Regulate Tumor Cell Invasion in a 3-D Tumor in Situ Model. Cancer microenvironment : official journal of the International Cancer Microenvironment Society, 9(2), 127-139. https://doi.org/10.1007/s12307-016-0188-z
McLane, Joshua S, and Ligon, Lee A. "Stiffened Extracellular Matrix and Signaling from Stromal Fibroblasts via Osteoprotegerin Regulate Tumor Cell Invasion in a 3-D Tumor in Situ Model." Cancer microenvironment : official journal of the International Cancer Microenvironment Society vol. 9,2 (2016): 127-139. doi: https://doi.org/10.1007/s12307-016-0188-z
McLane JS, Ligon LA. Stiffened Extracellular Matrix and Signaling from Stromal Fibroblasts via Osteoprotegerin Regulate Tumor Cell Invasion in a 3-D Tumor in Situ Model. Cancer Microenviron. 2016 Dec;9(2):127-139. doi: 10.1007/s12307-016-0188-z. Epub 2016 Sep 21. PMID: 27654881; PMCID: PMC5264661.
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Cancer Microenviron. 2016 Dec;9(2):127-139. doi: 10.1007/s12307-016-0188-z. Epub 2016 Sep 21.

Stiffened Extracellular Matrix and Signaling from Stromal Fibroblasts via Osteoprotegerin Regulate Tumor Cell Invasion in a 3-D Tumor in Situ Model.

Cancer microenvironment : official journal of the International Cancer Microenvironment Society

Joshua S McLane, Lee A Ligon

Affiliations

  1. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-5320, USA.
  2. Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY, 12180-3590, USA.
  3. Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, 12180-3590, USA.
  4. Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY, 12180-3590, USA. [email protected].
  5. Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, 12180-3590, USA. [email protected].

PMID: 27654881 PMCID: PMC5264661 DOI: 10.1007/s12307-016-0188-z

Abstract

Several changes have been described in the stroma surrounding a tumor, including changes in cellular composition, altered extracellular matrix composition and organization, and increases in stiffness. Tumor cells are influenced by the composition, organization, and mechanical properties of the microenvironment, and by signals from stromal cells. Here we sought to test whether signaling from stromal fibroblasts and/or the small change in stiffness observed in vivo surrounding epithelial tumors regulates tumor cell invasion from a model of a tumor in situ. We generated a novel tumor in situ model system in which a tumor spheroid is encased within a collagen-IV containing membrane and further encased within a collagen-I matrix of in vivo stiffness with or without fibroblasts. Effects of the matrix, fibroblasts or fibroblast signals were determined by observing the invasion of tumor cells into the matrix. Effects of reciprocal tumor cell signaling upon fibroblasts were determined by observing markers of fibroblast activation. We found that a stiffened matrix led to increased dissemination of MDA-MB-231 cells from tumor spheroids when no fibroblasts were present and that MCF10A cells maintained a more normal organization with a stiffened matrix. The presence of fibroblasts, or fibroblast conditioned media, attenuated the effect upon MDA-MB-231 cells. We also observed an attenuation of fibroblast activation associated gene expression in the presence of MDA-MB-231 cells, with a paradoxical increase in activation associated contractile activity. Furthermore, we identified osteoprotegerin as a soluble factor released by fibroblasts in the stiffened environment that is key to the inhibition of cell invasion.

Keywords: 3D hydrogel; Extracellular matrix; Invasion; Mechanotransduction; Tumor in situ

Conflict of interest statement

Compliance with Ethical Standards Competing Interests The authors declare no competing interests.

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