Prostate carcinoma skeletal metastases: Cross-talk between tumor and bone

Abstract

The majority of men with progressive prostate cancer develop metastases with the skeleton being the most prevalent metastatic site. Unlike many other tumors that metastasize to bone and form osteolytic lesions, prostate carcinomas form osteoblastic lesions. However, histological evaluation of these lesions reveals the presence of underlying osteoclastic activity. These lesions are painful, resulting in diminished quality of life of the patient. There is emerging evidence that prostate carcinomas establish and thrive in the skeleton due to cross-talk between the bone microenvironment and tumor cells. Bone provides chemotactic factors, adhesion factors, and growth factors that allow the prostate carcinoma cells to target and proliferate in the skeleton. The prostate carcinoma cells reciprocate through production of osteoblastic and osteolytic factors that modulate bone remodeling. The prostate carcinoma-induced osteolysis promotes release of the many growth factors within the bone extracellular matrix thus further enhancing the progression of the metastases. This review focuses on the interaction between the bone and the prostate carcinoma cells that allow for development and progression of prostate carcinoma skeletal metastases.

The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites

“…In a reciprocal relationship, PCa is believed to supply osteoblastic growth factors, such as vascular endothelial growth factor (VEGF) 98 and osteolytic factors that modulate bone remodeling. 96 At the same time, while osteoblastic activity is clearly the predominant feature of late stage of PCa metastasis, there is a significant component of osteoclastic activity in PCa. PCa-induced osteolysis may be due to both inhibitory effects on osteoblasts and stimulatory effects on osteoclasts by enhanced OPN secretion by osteoblasts.…”

“…Bone provides chemotactic factors, adhesion factors and growth factors that allow the PCa to target and proliferate in the bone. 96 CXCL12 is thought to activate proliferation of PCa cells. 20,21 On the other hand, neoplasm-derived factors have direct effects on osteoblasts differentiation and proliferation, the response of bone to neoplastic invasion and bone homeostasis.…”

Mortality following bone metastasis and skeletal-related events among men with prostate cancer: a population-based analysis of US Medicare beneficiaries, 1999–2006

“…About 70-80% of patients with metastatic prostate cancer present with or develop bone metastasis [2][3][4] and are at increased risk for skeletal-related events (SREs), which include pathological fractures, spinal cord compression and severe pain requiring radiotherapy or surgery for bone lesions. These SREs result in significant complications that reduce quality of life.…”

Interactions between microenvironment and cancer cells in two animal models of bone metastasis

“…On one hand, bone has characteristics that allow the selective homing of tumour cells: (1) a release of attractive molecules for these particular types of cancer (stromal cell-derived factor-1, epidermal growth factor, collagen degradation products, low glycosylated osteonectiny) inducing specific chemotaxis (Cooper et al, 2003); (2) the expression of adhesion molecule on the endothelial surface of bone marrow capillaries (due to a variety of integrins such as a4b1, a5b1, avb3, avb5) (Roodman, 2003); (3) appropriate growth factors and extracellular matrix proteins present in the bone marrow microenvironment (parathyroid hormone-related protein (PTHrP), tumour growth factor beta (TGF-b), vascular endothelium growth factor (VEGF)y) (Woodhouse et al, 1997;Guise and Mundy, 1998;Keller et al, 2001). On the other hand, these peculiar tumour cells express proteins that favour propensity to migrate and anchor in bone: this includes chemotaxis (CXCR4) (Muller et al, 2001), extravasation and bone marrow homing (integrins, E-cadherin) (Woodhouse et al, 1997), pericellular proteolysis and invasion (MMPs and ADAMs) (Woodhouse et al, 1997;Zigrino et al, 2005), angiogenesis (Woodhouse et al, 1997), osteoclastogenesis (Roodman, 2004), growth factor regulation (follistatin) (Risbridger et al, 2001;Reis et al, 2004) and extracellular matrix alteration (proteoglycan-1) (Timar et al, 2002).…”