Date of Award

2015

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Pathology and Laboratory Medicine

College

College of Graduate Studies

First Advisor

Steven L. Carroll

Second Advisor

Amanda C. LaRue

Third Advisor

Victoria J. Findlay

Fourth Advisor

Robert M. Gemmill

Fifth Advisor

Kris L. Helke

Sixth Advisor

Lee R. Leddy

Abstract

Soft tissue sarcomas (STS) are rare, malignant tumors of mesenchymal origin that manifest in the connective tissues, including muscle, adipose and deep skin tissue, nerves, and joint tissue. Complications from primary or recurrent sarcomas often lead to increased morbidity, but the most lethal aspect of sarcomas is their propensity for hematogenous dissemination leading to metastatic disease. After development of distant metastases, the median survival for patients with STS is merely 11 to 15 months1,2. Therefore, gaining a better understanding of the metastatic environment is essential to developing new therapies. The tumor microenvironment has been implicated as an essential component for metastatic progression and one of the most prominent cell types of the tumor microenvironment is the cancer-associated fibroblast (CAF)3,4. CAFs promote tumor progression by stimulating angiogenesis, cancer cell growth, invasion and metastasis, and through evasion of the immune response5,6. Studies clearly show the importance of CAFs in tumor advancement; however, their origins have not been conclusively determined, although multiple origins have been proposed7–12. Studies previously conducted in our lab have demonstrated that hematopoietic stem cells (HSCs) are a novel source for CAFs and their precursors in the blood, circulating fibroblast precursors (CFPs)13. Our lab has further shown that murine CFPs are present in peripheral blood, found in vivo in the tumor stroma, increase with tumor development, and contribute to tumor growth, suggesting that CFPs play a direct role in promoting the progression of solid tumors14. Additionally, studies from our lab revealed a HSC origin for human CFPs15. The function of human CFPs in tumor metastasis, specifically STS, however, has yet to be established. Therefore, the goal of this study was to evaluate the peripheral blood of patients with STS in order to characterize CFPs in these patients and determine their role in promoting STS metastatic progression. In this study, peripheral blood was collected from patients with STS and from normal control subjects. Our data has shown that CFPs are present within the peripheral blood of patients with STS and normal control subjects and that these cells display markers of fibroblasts, including collagen 1, alpha smooth muscle actin, and vimentin. Our data have also shown that although there is no significant difference in average number of CFPs present within the peripheral blood of STS patients compared to normal control, evaluating individual results indicated that patients with metastatic disease who are not on chemotherapeutic treatment may have increased numbers of CFPs. We further showed that CFPs from patients with STS contribute to sarcoma cell proliferation, migration, and invasion in vitro and that in vitro generated tumor-exposed CFPs showed enhanced ability to contribute to sarcoma invasion and displayed an altered cytokine profile when compared to control CFPs. Our data indicate CFPs may play an important role in tumor progression and that through further analysis, it may be discovered that these differences are subtype, tumor stage, and treatment dependent.

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