Prostate Cancer Phenotype Influences Bone Mineralization at Metastasis: A Study Using an In Vitro Prostate Cancer Metastasis Testbed

Abstract

In this study, two types of prostate cancer cell lines, highly metastatic PC‐3 and low metastatic MDA PCa 2b (PCa) were cultured on bone mimetic scaffolds to recapitulate metastasis to bone. A unique in vitro 3D tumor model that uses a sequential culture (SC) of human mesenchymal stem cells followed by seeding with cancer cells after bone formation was initiated to study the phenotype‐specific interaction between prostate cancer cells and bone microenvironment. The PCa cells were observed to be less prolific and less metastatic, and to form multicellular tumoroids in the bone microenvironment, whereas PC‐3 cells were more prolific and were highly metastatic, and did not form multicellular tumoroids in the bone microenvironment. The metastatic process exhibited by these two prostate cancer cell lines showed a significant and different effect on bone mineralization and extracellular matrix formation. Excessive bone formation in the presence of PC‐3 and significant osteolysis in the presence of PCa were observed, which was also indicated by osteocalcin and MMP‐9 expression as measured by ELISA and qRT‐PCR. The field emission scanning electron microscopy images revealed that the structure of mineralized collagen in the presence of PC‐3 is different than the one observed in healthy bone. All experimental results indicated that both osteolytic and osteoblastic bone lesions can be recapitulated in our tumor testbed model and that different cancer phenotypes have a very different influence on bone at metastasis. The 3D in vitro model presented in this study provides an improved, reproducible, and controllable system that is a useful tool to elucidate osteotropism of prostate cancer cells. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Major surgery-induced expansion of myeloid-derived suppressor cells promotes breast cancer cell bone metastasis though PD-1

“…As demonstrated by previous experiments, microenvironment of distant organ can exert inhibitory effects on aggressive malignant cells at the early stage of tumor development [2]. However, the protective restraints of the microenvironment are overridden by pathological conditions such as stress, chronic in ammation [4].…”

“…Although surgical removal of primary tumors can extend or save life, it is well known that surgery itself may accelerate tumor metastasis [1]. Bone is the most common organ of metastasis especially in patients with breast and prostate cancer [2].…”

“…Then the local microenvironment shifts to a growth-promoting state. It has been well demonstrated that surgery caused severe stress and systemic in ammation, which subsequently in uenced the bone marrow microenvironment [2]. Whether these factors modulate metastatic tumor growth in bone microenvironment has yet to be fully elucidated.…”

“…It is well known that major surgery induces suppressed cellular immunity as evidenced by decreased circulating levels of anti-tumor immune cells, such as natural killer (NK) cells, T-helper (Th) cells and cytotoxic T lymphocytes (CTLs) [2]. Moreover, surgery also increased the amount of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) [2].…”

<p>Role of αVβ3 in Prostate Cancer: Metastasis Initiator and Important Therapeutic Target</p>

“…Pathologically, PCa bone metastasis is classified as an osteolytic disease. 101 Runx2 is a transcription factor that plays a key regulatory role in osteoblast differentiation. 102,103 DNA sequencing found that the receptor activator of nuclear factor kB ligand (RANKL) contains a Runx2 binding site in the promoter region.…”