Molecular Pathway for Cancer Metastasis to Bone

Abstract

The molecular mechanism leading to the cancer metastasis to bone is poorly understood but yet determines prognosis and therapy. Here, we define a new molecular pathway that may account for the extraordinarily high osteotropism of prostate cancer. By using SPARC (secreted protein, acidic and rich in cysteine)-deficient mice and recombinant SPARC, we demonstrated that SPARC selectively supports the migration of highly metastatic relative to less metastatic prostate cancer cell lines to bone. If prostate cancer is locally confined, the 5-year survival rate is nearly 100%; however, if the cancer metastasizes to distant sites, the 5-year survival rate is only 31%. Bone is by far (80 -85%) the primary site of prostate cancer metastasis. Despite the high incidence and serious consequences of skeletal metastasis of prostate cancer, the mechanisms underlying this osteotropism are poorly understood. However, it is clear that bone-specific matrix proteins and their receptors on the surface of prostate cancer cells play a pivotal role in the process (1-3). Recent analysis of bone extracts has revealed that a key factor that mediates prostate cancer cell invasion is the protein osteonectin or SPARC 1 (secreted protein, acidic and rich in cys-

Elevated osteonectin/SPARC expression in primary prostate cancer predicts metastatic progression

“…Our results from GeneChip analysis and quantitative evaluation of SPARC mRNA expression in 110 CaP patients are consistent with the literature that indicates a role for SPARC, 22,23 and a high expression of SPARC protein 20 , in metastasis. Therefore, we hypothesized that high SPARC expression (likely at protein level as SPARC is functionally linked to metastasis) in primary prostate tumors may predict a higher chance of later metastasis.…”

“…Of note, there was conservation of NKXH_NKXH_HOX composite regulatory elements in the promoters of the genes in this network suggestive of the biological significance of this gene-expression regulatory mechanism in CaP progression. As SPARC has a role 22,23 and high protein levels 20 in metastasis, we hypothesized that high SPARC expression in primary tumor may predict future metastasis. Indeed, further analysis revealed that high SPARC protein expression in malignant prostate cells at the time of RP is associated with an increased risk of tumor metastasis (see study flow chart in Supplementary Figure 2).…”

“…The SPARC gene (also known as osteonectin or BM-40) is mapped to chromosome 5q31.3 and linked to bone metastasis. 22 The sequence is highly conserved between species and codes for a 32 000-dalton secreted matrix-associated glycoprotein. SPARC plays an important role in cell-matrix interactions, tissue remodeling, wound repair, cellular differentiation, morphogenesis, cell migration and angiogenesis.…”

Normalization of the Ovarian Cancer Microenvironment by SPARC

“…Recent reports highlight the role of this molecule as a positive or negative modulator in the pathogenesis of different malignancies (18)(19)(20)(21)(22)(23)(24). We and others have shown that SPARC functions as a tumor suppressor in ovarian cancer (25)(26)(27)(28).…”

“…VEGF is known to exert an autocrine as well as paracrine mitogenic effect on a variety of tumor cells including melanoma, prostate cancer, and ovarian cancer in vivo (22,(35)(36)(37)(38). Our pilot studies indicated that VEGF stimulates the proliferation of ID8 cells in a concentration-dependent manner (data not shown).…”