Tumor-associated myeloid cells convert indolent prostate cancer to aggressive disease

Abstract

Abstract Difficulties differentiating indolent from progressing prostate cancer (CaP) results in ineffective treatment strategies. Tumor-associated myeloid cells (TAMC) contribute to tumor progression; yet the role TAMC play in the conversion from indolent to progressing CaP is unclear. To test whether TAMC promote CaP progression we developed a murine model using two isogenic cell lines from the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. Tumorigenic C2 cells mimic progressing disease while non-tumorigenic C3 cells represent indolent disease. We report for the first time that CD11b+ TAMC isolated from C2 tumors co-injected with the non-tumorigenic C3 cells drive C3 tumor growth. In contrast, TAMC isolated from C2 tumor-bearing spleens or naïve spleens did not promote C3 tumor growth. This is the first indication that TAMC drive progression of indolent disease. Strikingly, tumor cells explanted from TAMC-induced C3 tumors were tumorigenic in the absence of additional TAMC, suggesting that TAMC induce stable changes within the C3 cells. These results have been recapitulated with the non-tumorigenic human cell line BPH-1 (benign prostatic hyperplasia). Furthermore, TAMC-induced tumor growth occurs via a TAMC secreted factor. Using a 5-day transwell system PC3M (human prostatic adenocarcinoma) TAMC were able to drive BPH-1 tumorigenesis. Future work will determine the factor secreted by TAMC and identify the molecular mechanisms responsible for tumor promotion. This work has the potential to identify critical factors responsible for the conversion of indolent to progressing disease thus laying the groundwork for novel prognostic and therapeutic strategies.