Abstract B28: Signaling by PDGF-CC in the maintenance of a protumorigenic breast cancer microenvironment

It is increasingly appreciated that cancer results from the concerted performance of genetically altered tumor cells interacting with ostensibly normal cells in the microenvironment. As the cancer progresses, the surrounding stroma co-evolves into an activated state through continuous paracrine communication, thus creating a dynamic signaling circuitry that promotes cancer initiation and growth, and ultimately leads to a fatal disease. We aim to molecularly map the support functions performed by the various cell types comprising the tumor stroma. Specifically we will focus on, cancer-associated fibroblasts (CAFs), which are known to support many aspects of tumor progression. Based on our previous finding that paracrine signaling by Platelet-derived growth factor (PDGF)-CC serves to recruit CAFs into tumors we have generated Pdgfc -deficient genetically engineered mouse models of breast cancer. Our results show a significant reduction in the tumor burden followed by prolonged survival in the absence of PDGF-CC, in agreement with the recent finding that PDGF-CC expression is an indicator of poor prognosis for breast cancer patients. Upon transplantation of small tumor pieces from wildtype and Pdgfc -deficient tumors respectively into the mammary fatpad of wildtype mice, Pdgfc -deficient tumors show substantial growth retardation with massive hemorrhage and necrosis, indicative of malfunctional vessels and insufficient blood supply. qPCR arrays on total RNA from wildtype and Pdgfc -deficient tumors respectively, suggest that lack of PDGF-CC causes perturbed differentiation yielding a less advanced tumor. Furthermore, we are currently investigating the differences observed in the recruited fibroblasts and/or MSCs in wildtype and Pdgfc -deficient tumors, by performing proteomics on isolated PDGFR-α positive cells. Tumor morphology in combination with proteomics suggests that the lack of PDGF-CC causes an impaired migration and/or guidance of the recruited fibroblasts from the periphery of the tumor. Thus, our studies suggest a novel role for PDGF-CC in creating a pro-tumorigenic microenvironment and identify PDGF-CC as a valid and promising therapeutic target in breast cancer. Citation Format: Pernilla Roswall, Kristian Haller, Annika Petersson, Charlotte Anderberg, Hong Li, Jens-Henrik Norum, Rune Toftgard, Ulf Eriksson, Kristian Pietras. Signaling by PDGF-CC in the maintenance of a protumorigenic breast cancer microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B28.