Abstract IA17: Development of a therapeutic peptide for the treatment of metastatic cancer
Authors: Watnick Randolph S. , Mittal Vivek , Catena Raul , Wang Suming , Reyes Tina El , Akslen Lars 
Published: August 2014

Abstract
The progression of human cancer to the metastatic stage is a major contributing factor to its lethality. In order for a tumor to form lethal metastases it must gain access to the vasculature or lymphatic system (intravasation), survive during transit, exit the vascular or lymphatic channels (extravasation), and proliferate at the metastatic site. Upon colonization of a distant tissue, tumor cells must, once again, induce neovascularization in order to grow beyond a microscopic size. In this process, heterotypic tumor-stromal signaling can affect tumor growth by regulating the production and secretion of growth-promoting and growth-inhibitory proteins by the surrounding stromal fibroblasts and endothelial cells. For example, it has been previously demonstrated that tumor cells can stimulate expression of the pro-angiogenic protein VEGF in the surrounding stroma. Conversely, the regulation of thrombospondin-1 (Tsp-1) expression, one of the most potent endogenous anti-angiogenic proteins, in the tumor-associated stroma, has not been as well studied. Through a functional proteomic screen, designed to identify secreted proteins that stimulate Tsp-1 in tumor stroma and in the parenchyma of distant tissues, we identified the protein, prosaposin (1).
With respect to the role of the tumor micro-environment in metastasis, it has been demonstrated that metastatic tumors establish bone marrow (BM)-derived pre-metastatic niches in distant organs that serve as permissive hubs for supporting future metastases. It is not known, conversely, whether tumors that lack metastatic potential fail to establish such niches, or generate niches which inhibit metastasis. Here, we show that metastasis-incompetent tumors are also capable of generating BM-derived niches at distant sites. However, by secreting prosaposin (psap) these tumors systemically stimulate expression of an antiangiogenic factor thrombospondin1 (Tsp-1) in myeloid progenitor cells in the niche, converting them into metastasis-inhibitory cells. We found that the Tsp-1-inducing activity of psap was contained in a short peptide. Importantly this peptide is able to suppress metastatic outgrowth and regress existing metastases. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential, and unexpectedly implicate recruited Gr1+ myeloid progenitor cells as the main source of Tsp-1 in the metastatic lung. Clinically, psap expression was significantly decreased in skeletal metastases in prostate cancer patients, suggesting that the psap peptide may be a potential therapeutic agent against metastatic cancer.
Citation Format: Randolph S. Watnick, Vivek Mittal, Raul Catena, Suming Wang, Tina El Reyes, Lars Akslen. Development of a therapeutic peptide for the treatment of metastatic cancer. [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 IA17.