Abstract 5077: Cancer-associated fibroblasts stimulate tumor growth and metastatic spread in an orthotopic prostate cancer xenograft model

Abstract

Abstract Introduction: In recent years, it has become more and more evident, that the different cell populations comprising the so-called “tumor microenvironment” contribute substantially to the processes of carcinogenesis, local tumor growth and metastatic spread. Especially the tumor-promoting roles of cancer-associated fibroblasts have been the focus of several elaborate in-vitro studies. However, evidence from representative in-vivo models is scarce. In this study, we coinjected prostate cancer (PCa) cells together with different populations of prostate fibroblasts (cancer-associated (CAF), not cancer-associated (NCAF), benign prostate hyperplasia associated (BPHF)) and examined their impact on local tumor growth and the development of metastases. Material & Methods: We isolated fibroblast primary cultures from tumor-bearing (CAF) and tumor-free (NCAF) tissue samples of a radical prostatectomy specimen as well as from tissue samples of a transvesical prostate adenoma enucleation (BPHF). 5x105 CAF/NCAF/BPHF cells were injected into the prostate of SCID mice together with 5x105 LuCaP136 spheroids or LNCaP cells (n=8 for each group). Tumor growth was monitored by high-resolution ultrasonography (hrUS), micro-CT, 9.4T MRI and serum PSA-measurements. Animals were sacrificed after 10 weeks. Results: The coinjection of CAFs fostered tumor growth in LuCaP136 but not in LNCaP xenografts. Primary tumor volumes were significantly higher in LuCaP136+CAF mice compared to LuCaP136+NCAF and LuCaP136+BPHF mice (p<0.01 for each time point). Besides that, LuCaP136+CAF mice had significantly higher serum PSA values than their NCAF and BPHF counterparts (p<0.01 for each time point). Significantly more lymph node metastases (LN mets) were seen in LuCaP136+CAF mice (one mouse without, four mice with 2 and three mice with ≥3 LN mets) compared to LuCaP136+NCAF (one mouse without, four mice with 1 and one mouse with 2 LN mets) and LuCaP136+BPHF mice (two mice without, three mice with 1 and two mice with 2 LN mets) (p<0.01). Furthermore, pulmonary metastases were observed more often in LuCaP136 and LNCaP xenografts when PCa cells were coinjected with CAFs (57% for LuCaP136, 71% for LNCaP) as compared to coinjection with NCAFs (0% for LuCaP136, 29% for LNCaP) and BPHFs (14% for LuCaP136, 29% for LNCaP). Conclusions: Using a representative orthotopic xenograft model and patient-derived fibroblast primary cultures it could be shown that CAFs play a crucial role in local and systemic PCa progression by stimulating primary tumor growth as well as metastatic spread to the lymph nodes and lungs. However, some of the effects were cell-line specific. Future experiments will have to focus on the reproduction of these observations with the use of further sets of fibroblast primary cultures and on the unraveling of the molecular mechanisms underlying the crosstalk between PCa cells and CAFs. Citation Format: Johannes Linxweiler, Markus Hammer, Christina Körbel, Andreas Müller, Michael Stöckle, Michael D. Menger, Kerstin Junker, Matthias Saar. Cancer-associated fibroblasts stimulate tumor growth and metastatic spread in an orthotopic prostate cancer xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5077.