Abstract IA24: How tumors regulate their microenvironment in primary sites and metastasis
Authors: Casbon Amy Jo , Lohela Marja , Plaks Vicki , Werb Zena 
Published: May 2015

In 1863, Virchow hypothesized that the cancer originated at sites of chronic tissue injury and that the ensuing inflammation they cause enhances cell proliferation. While it is now clear that proliferation of tumor cells alone does not cause cancer, sustained cell proliferation in an environment rich in inflammatory cells, growth factors, activated stroma certainly potentiates and/or promotes neoplastic risk and leads to metastasis. In fact, sometimes the trigger for neoplastic progression may come from signals within the stromal microenvironment. The stromal microenvironment consists of fibroblasts, macrophages, neutrophils, vascular components, nerves and inflammatory cells of the innate and acquired immune response, as well as the extracellular matrix that they elaborate along with the molecules that are concentrated and immobilized on it. All of these components communicate with each other and with the neoplastic cells to contribute to the aberrant tumor organ. Factors elaborated by tumors cause dramatic increases in inflammatory myeloid cells in the microenvironment of the primary tumor as well as in distant sites upon the malignant conversion of the tumor cells. These myeloid cells modulate the tumor ecology and regulate metastatic take, altering vascular permeability and responses to chemotherapy. The dynamic interplay of tumor cells and host cells responding to the tumor in the microenvironment contribute to tumor evolution, metastasis and evasion of therapeutic responses.

Supported by grants from the National Cancer Institute.

Chou, J., J.H. Lin, A. Brenot, J.-w. Kim, S. Provot & Z. Werb (2013). GATA3 suppresses metastasis and modulates the tumor microenvironment by regulating miR-29 expression. Nat. Cell Biol. 15: 201-213. [2013 Jan 27, PMCID: PMC3660859.

Chou, J., P. Shahi & Z. Werb (2013). MicroRNA-mediated regulation of the tumor microenvironment. Cell Cycle. In press.

Egeblad, M., A. J. Ewald, H. A. Askautrud, B. E. Welm, M. Truitt, E. Bainbridge, G. Peeters, M. Krummell & Z. Werb (2008). Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy. Dis. Model. Mech. 1:155-167. PMCID: PMC2562195.

Egeblad, M., N. Nakasone & Z. Werb (2010). Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell. 18:884-901. PMCID: PMC2905377.

Kessenbrock, K., V. Plaks & Z. Werb (2010). Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell. 141: 52-67. PMCID: PMC286205.

Kessenbrock, K., G.J.P. Dijkgraaf, D. A. Lawson, L. E. Littlepage, P. Shahi, U. Pieper & Z. Werb (2013). A role for matrix metalloproteinases in regulating mammary stem cell function via the Wnt signaling pathway. Cell Stem Cell. [Epub ahead of print July 18]. PMID: 23871604.

Kouros-Mehr, H., S. K. Bechis, E.M. Slorach, L. E. Littlepage, M. Egeblad, A. J. Ewald, S.-Y. Pai, I-C. Ho & Z. Werb (2008). GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell. 13:141-152. PMCID: PMC2262951.

Littlepage, L. E., M. D. Sternlicht, N. Rougier, J. Phillips, E. Gallo, Y. Yu, K. Williams, A. Brenot, J. I. Gordon & Z. Werb (2010). Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression. Cancer Res. 70:2224-2234. PMCID: PMC2840052.

Littlepage, L.E., A. S. Adler, H. Kouros-Mehr, G. Huang, J. Chou, S. R. Krig, O. L. Griffith, J. E. Korkola, K. Qu, D. A. Lawson, Q. Xue, M. D. Sternlicht, G. J. P. Dijkgraaf, P. Yaswen, H. S. Rugo, C. A. Sweeney, C. C. Collins, J. W. Gray, H. Y. Chang & Z. Werb (2012). The transcription factor ZNF217 is a prognostic biomarker and therapeutic target during breast cancer progression. Cancer Discov. 2 : 638-651. PMCID : PMC3546490.

Lu, P., V. M. Weaver & Z. Werb (2012). Extracellular matrix: a dynamic niche component during cancer progression. J. Cell Biol. 196:396-406. PMCID: PMC3283993.

Nakasone, E., H. A.Askautrud, T. Kees, V. Plaks, A. J. Ewald, M. G. Rasch, Y. X. Tan, J. Qin, M. Fein, J. Park, P. Sinha, M. J. Bissell, E. Frengen, Z. Werb & M. Egeblad (2012). Imaging tumor-stroma interactions during chemotherapy reveals microenvironmental contributions to chemoresistance. Cancer Cell. 21:488-503. PMCID: PMC3332002.

Nguyen-Ngoc, K.-V., K. J. Cheung, A. Brenot, E. R. Shamir, R. S. Gray, W. C. Hines, P. Yaswen, Z. Werb* & A. J. Ewald* (2012). The ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium. Proc. Natl. Acad. Sci. USA. 109:E2595-E2604. PMCID: PMC3465416.

Sounni, N. E., K. Dehne, L. van Kempen, M. Egeblad, N.I. Affara, I. Cuevas, J. Wiesen, J. Junankar, L. Korets, L. Lee, J. Shen, C. J. Morrison, C. M. Overall, S. M. Krane, Z. Werb, N. Boudreau & L. M. Coussens (2010). Stromal regulation of vessel stability by MMP9 and TGFβ. Dis. Model. Mech. 3: 317-332. PMCID: PMC20223936.

Citation Format: Amy Jo Casbon, Marja Lohela, Vicki Plaks, Zena Werb. How tumors regulate their microenvironment in primary sites and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA24.