Carcinoma-Associated Fibroblasts from African American Prostate Cancer Promote Aggressive Tumors: Implications for Developing Novel Therapy
Abstract
Prostate cancer (PCa) in African American (AA) men is more aggressive, leads to greater treatment failure, and has a two- to three-fold greater mortality compared to PCa of European American (EA) men. The mechanism of how race contributes to aggressive PCa in AA patients is not understood. Whole genome or exome tumor-sequencing studies have shown that the majority of tumors from AA men harbor significantly less genomic alterations or mutations in known cancer driver genes than described in EA patients. Our gene expression profiling study of fresh frozen prostatectomy specimens of AA and EA PCa patients matched for tumor content have observed that only 56 (7.4%) differentially expressed genes are associated with tumor tissue and 677 (92.4%) in stroma tissue. This result leads us to believe as one possibility that the aggressive nature of AA PCa patients may partly reside in differences in the molecular properties of the stroma of AA versus EA PCa patients. To test this idea, we have developed 101 pairs of primary carcinoma-associated fibroblasts (CAFs) and distant CAFs (dCAFs) and 8 autologous prostate tumor organoid cultures from fresh prostatectomy specimens of AA and EA PCa patients. In sub-renal capsule xenograft of CAFs and non-tumorigenic BPH-1 prostate epithelial cells in the severe combined immunodeficiency mice, our preliminary data have shown that 8 of the 10 AA CAF/BPH-1-inoculated mice developed large tumors; two of these mice developed liver metastases; and none of the 5 EA CAF/BPH-1-inoculated mice developed tumors. These results suggest that stroma may play a critical role in the aggressiveness of AA PCa. To substantiate and generalize these preliminary data, we will carry out more rigorous tumorigenicity experiments in Aim 1 to determine the differential ability of AA CAFs versus EA CAFs to transform BPH-1 cells and the normal mouse prostate into tumorigenic products. If the stronger impact of AA CAFs on tumorigenesis compared to EA CAFs can be validated, new cell resources in the form of multiple partially characterized patient-derived stroma cells from AAs not previously available for study can be used to dissect the factor(s) of the stroma cells that contribute to PCa and, particularly, factors involved in aggressive PCa that is more prevalent in AAs. In addition, a specific molecular target, L-3-phosphoserine phosphatase (PSPH), was identified from our gene expression profiling analysis of large clinical specimens. PSPH is a key enzyme for synthesis of serine and nucleotides to promote cancer cell proliferation, and collagen deposition in tumor microenvironment is regulated by TGF-beta/PSPH signaling. PSPH is also amplified in lethal castration resistant PCa and predicts poor survival of PCa patients. Therefore, in Aim 2, we will determine the impact of the enzymatic activity or expression of PSPH and high serine production on in vivo tumor growth. The understanding of the necessity of PSPH enzymatic activity and its expression for the initiation of in vivo tumor growth will provide a basis for designing novel PSPH inhibitors to target both PCa tumor and stroma, particularly in AAs. Furthermore, tumor stroma represents significant barriers to effective delivery of therapeutic drugs into prostate tumors. The goal of Aim 3 is to develop a “proof-of-principal” nanoparticle-based therapy to address this unmet clinical challenge presented in tumor microenvironment of PCa, particularly for AAs. This nanoparticle engineering is to construct a multifunctional nanoparticle to target specific biological factors in the tumor microenvironment. Two different encapsulation methods are integrated in a single particle to provide precisely tailored drug release kinetics: first, clear the way for access by depleting the stroma using a TGF-beta inhibitor, followed by a second drug (docetaxel) release that is meant for killing the tumor. Our long-term goal is integrated by using our newly developed
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910726
Entities
People
- Xiaolin Zi
Organizations
- United States Army
- University of California, Irvine