Abstract 1954: Human circulating progenitor cells of hematopoietic origin promote tumor growth in melanoma xenograft models

Abstract

Abstract The tumor microenvironment contains various cell sub-populations of hematopoietic and endothelial origin. These cells are recruited by the tumor and can play an integral role in regulating tumor growth and metastasis. However, the heterogeneity of these cells has made it difficult to study their specific function in tumorigenesis. We recently developed a detailed polychromatic flow cytometric (PFC) protocol to isolate and characterize the phenotype of the hematopoietic versus endothelial circulating progenitor cells (CPCs) found in peripheral blood (PB). Transplantation of CPC populations into NOD/SCID mice indicated that a purported endothelial CPC subset largely consisted of in vivo engrafting hematopoietic stem cells and myeloblasts, and not endothelial cells. Additionally, our recent PFC studies indicate that hematopoietic CPCs can be subdivided into two cell populations based upon AC133 expression (ViViD−CD14−glyA−CD34+AC133+CD45dimCD31+ and ViViD−CD14−glyA−CD34+AC133−CD45dimCD31+ cells), and will be referred to as primitive CPCs and mature CPCs respectively. To date, the functional role of hematopoietic CPCs in tumor growth is not known. We hypothesize that primitive CPCs home to the tumor bed and secrete pro-angiogenic factors to promote tumor growth. To address this hypothesis, we have developed two in vivo modeling approaches. In the first approach, primitive and mature CPCs were isolated from umbilical cord blood CD34+ cells and intravenously injected into NOD/SCID mice harboring C32 human melanoma xenografts that secrete high levels of vascular endothelial growth factor. Tumor growth was monitored for 7 weeks and a statistically significant increase in melanoma growth and weight was observed in mice injected with the primitive CPCs compared to control mice (p<0.001, primitive CPCs vs mature CPCs, phosphate buffered saline or non-sorted CD34+ cells). Histological analyses did not detect human CD34+, AC133+, or CD31+ cells in the tumor xenograft tissue at week 7. Time-course studies are in progress to determine if human hematopoietic cells can be found in the tumor bed during the early stages of tumor growth. In the second approach, sub-lethally irradiated NOD/SCID mice were first transplanted with human CD34+ cells and detectable levels of primitive CPCs in the PB were observed at one month post-transplantation. C32 melanoma cells were then injected subcutaneously into the flank and tumor growth monitored. At 3-4 weeks post-tumor implantation, melanoma xenografts began to grow more rapidly in mice previously transplanted with human CD34+ cells compared to melanoma xenografts in sub-lethally irradiated, non-transplanted mice. Taken together, these data indicate that primitive human CPCs of hematopoietic origin play a functional role in tumorigenesis and the in vivo models developed here can be used to delineate how hematopoietic CPCs regulate tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1954.