Abstract A46: The role of circulating fibroblast precursors in promoting metastatic sarcoma
Authors: Laws Dayvia A. , Kraft Andrew S. , Leddy Lee R. , LaRue Amanda C. 
Published: May 2015

Soft tissue sarcomas are malignant tumors that develop in connective tissue. Treatment with standard chemotherapeutic agents is often minimally effective and approximately half of all patients with soft tissue sarcoma experience disease recurrence and die of metastatic cancer. Therefore, the purpose of this study is to gain a better understanding of the soft tissue sarcoma metastatic environment in order to lead to the development of more effective therapies. Studies have shown that the tumor microenvironment plays a pivotal role in promoting tumor metastasis and one of the most prominent cell types of the tumor microenvironment is the carcinoma associated fibroblast (CAF). Our studies, based upon a murine single hematopoietic stem cell transplantation model have demonstrated that hematopoietic stem cells (HSCs) are a novel source for CAFs and their circulating fibroblast precursors (CFPs). Our research has also shown that murine CFPs are present in the peripheral blood, increase with tumor burden, and contribute to tumor growth. In vitro studies have shown that HSC-derived CFPs enhance tumor cell proliferation, migration, and invasion, processes critical to tumor metastasis in vivo. The role of human CFPs in metastasis of soft tissue sarcoma, however, has yet to be determined. It is our hypothesis that HSC derived CFPs promote sarcoma cell proliferation, migration, and invasion. In order to determine the role of CFPs in sarcoma metastasis, we established a method for culturing fibroblasts from peripheral blood obtained from patients diagnosed with metastatic sarcoma. These cultured cells were then characterized by immunohistochemistry to profile fibroblast and hematopoietic markers. In order to address the functional role of CFPs during sarcoma metastasis, we examined the ability of conditioned media from cultured CFPs from patients with metastatic sarcoma to influence the proliferation, migration, and invasion of HT-1080 cells, a human sarcoma line. Our immunohistochemical findings demonstrate that fibroblasts can be isolated from the circulation of patients with metastatic sarcoma and results from our functional assays indicate that cultured CFPs from patients with metastatic sarcoma promote the proliferation, migration, and invasion of HT-1080 cells. Given that proliferation, migration, and invasion of tumor cells are essential steps in the metastatic cascade, these findings suggest that CFPs promote tumor progression. Ongoing studies involve analysis of CFPs at various time points based upon chemotherapeutic treatment in order to evaluate differences in numbers of CFPs, marker expression, growth factor production, and ability to promote metastasis. Long term, these studies may identify novel biomarkers for disease progression as well as treatment efficacy, potentially leading to the development of more effective therapies for soft tissue sarcomas.

Citation Format: Dayvia A. Laws, Andrew S. Kraft, Lee R. Leddy, Amanda C. LaRue. The role of circulating fibroblast precursors in promoting metastatic sarcoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A46. doi:10.1158/1538-7445.CHTME14-A46