The Host Microenvironment Influences Prostate Cancer Invasion, Systemic Spread, Bone Colonization, and Osteoblastic Metastasis

Abstract

Prostate cancer (PCa) is the second leading cause of cancer death in men worldwide. Most PCa deaths are due to osteoblastic bone metastases. What triggers PCa metastasis to the bone and what causes osteoblastic lesions remain unanswered. A major contributor to PCa metastasis is the host microenvironment. Here, we address how the primary tumor microenvironment influences PCa metastasis via integrins, extracellular proteases, and transient epithelia-mesenchymal transition (EMT) to promote PCa progression, invasion, and metastasis. We discuss how the bone-microenvironment influences metastasis; where chemotactic cytokines favor bone homing, adhesion molecules promote colonization, and bone-derived signals induce osteoblastic lesions. Animal models that fully recapitulate human PCa progression from primary tumor to bone metastasis are needed to understand the PCa pathophysiology that leads to bone metastasis. Better delineation of the specific processes involved in PCa bone metastasize is needed to prevent or treat metastatic PCa. Therapeutic regimens that focus on the tumor microenvironment could add to the PCa pharmacopeia.

Radium-223: Insight and Perspectives in Bone-metastatic Castration-resistant Prostate Cancer

“…This is a complex mechanism, not yet fully understood and involving many non-tumoral cell types and a cascade of events mediated by several cytokines and chemokines that drive PCa metastasis to the bone. Hormones and peptides derived from cancer cells drive osteoblasts to produce RANKL for bone resorption (72).…”

“…Why PCa prefers bone as a site for metastasis, why metastasis is predominantly blastic, and what initiates tumor metastasis remain partially unexplained (72).…”

Human Bone Xenografts: from Preclinical Testing for Regenerative Medicine to Modeling of Diseases

“…Once homed to bone marrow, tumor cells have been shown to interact with MSC or with their progeny (such as osteoblasts and adipocytes) to induce both pro-tumorigenic and inhibitory effects [81][82][83]. In light of such findings, it is clear that early crosstalk between disseminated tumor cells and the bone microenvironment is key to metastatic activation and disease progression [84], highlighting an urgent unmet need for adequate models of the disease.…”

The Role of EphB4 and Ephrin-B2 Interactions in Prostate Cancer Models of Intravasation and Extravasation

“…Studies have also shown that bidirectional EphB4-ephrin-B2 signalling has a paracrine role in osteoclast and osteoblast communication, regulating differentiation and bone formation/resorption. This is particularly interesting since PCa metastases usually occur within the bone [115]. Bone homeostasis relies on an intricate balance between bone-resorbing osteoclasts, which express ephrin-B2, and bone-forming osteoblasts, which express EphB4 [115,116].…”

“…This is particularly interesting since PCa metastases usually occur within the bone [115]. Bone homeostasis relies on an intricate balance between bone-resorbing osteoclasts, which express ephrin-B2, and bone-forming osteoblasts, which express EphB4 [115,116]. EphB4 and ephrin-B2 have an imperative role in regulating the differentiation of osteoclasts and osteoblasts through suppression of bone resorption and enhancing bone formation [116].…”