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In order to develop new approaches for treatment of aggressive cancers, it is necessary to attain a better understanding of their development and progression. One poorly studied aspect of tumorigenesis is the nature of tumor-stromal interactions. It has become clear that the tumor microenvironment (including stromal fibroblasts, infiltrating immune and inflammatory cells, blood and lymphatic vascular network, and the extracellular matrix) is an integral part of the carcinogenic process promoting cell growth and metastases. Benign epithelial tumors are constrained by a surrounding stroma consisting of fibroblastic cells and a fibrillar three-dimensional extracellular matrix. These ‘normal’ fibroblasts and their matrices assist in maintaining a homeostatic equilibrium, exerting an inhibitory effect on the epithelial cells undergoing malignant changes. However, tumor-generated paracrine signaling alters and overcomes this stromal barrier, inducing changes in the local mesenchymal microenvironment that promote rather than impede tumor progression.

In our laboratory, we isolate primary fibroblasts from various murine and human cancers at different stages of tumorigenesis. Using these fibroblasts, we have developed a three-dimensional in vivo-like stromal system, which is used to conduct our studies. Research is directed at better understanding the role of tumor-associated stroma in cancer invasion and metastasis. We aim to understand how tumor cells alter the local mesenchymal microenvironment, at both primary and secondary (e.g., metastatic) niches, in a way that this stroma supports and incites (instead of constraining) tumor progression (e.g., cancer cell invasion). Our group also uses this three-dimensional culturing system as an approach to improve the preclinical cancer drug-development process, believing that stromal microenvironment can significantly alter the efficacy of drugs in evaluation or currently in use for cancer treatment. For this, our laboratory is carrying out analyses that incorporate biochemical, molecular and cell biology assays, laser scanning confocal and real time microscopy, digital analyses, as well as tissue patterning approaches.

1. Castelló-Cros R, Khan DR, Simons J, Valianou M, Cukierman E. Staged stromal extracellular 3D matrices differentially regulate breast cancer cell responses through PI3K and beta1-integrins. BMC Cancer. 2009 Mar 26;9:94. PubMed
2. Castelló-Cros R, Cukierman E. Stromagenesis during tumorigenesis: characterization of tumor-associated fibroblasts and stroma-derived 3D matrices. Methods Mol Biol. 2009;522:275-305. PubMed
3. Quiros RM, Valianou M, Kwon Y, Brown KM, Godwin AK, Cukierman E. Ovarian normal and tumor-associated fibroblasts retain in vivo stromal characteristics in a 3-D matrix-dependent manner. Gynecol Oncol. 2008 Jul;110(1):99-109. PubMed
4. Serebriiskii I, Castello-Cros R, Lamb A, Golemis EA, and Cukierman E. Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells. Matrix Biology. 2008;27:573-585. PubMed
5. Yamada KM, Cukierman E. Modeling tissue morphogenesis and cancer in 3D. Cell. 2007 Aug;130(4):601-10. PubMed
6. Amatangelo MD, Bassi DE, Klein-Szanto AJ, Cukierman E. Stroma-derived three-dimensional matrices are necessary and sufficient to promote desmoplastic differentiation of normal fibroblasts. Am J Pathol. 2005;167(2):475-88. PubMed
7. Cukierman E, Pankov R, Stevens DR, and Yamada KM. Taking cell-matrix adhesions to the third dimension. Science. 2001;294:1708-1712. PubMed