Pathogenic Role of Connective Tissue Growth Factor (CTGF/CCN2) in Osteolytic Metastasis of Breast Cancer

Abstract

CCN2 was critically involved in osteolytic metastasis and was induced by PKA- and PKC-dependent activation of ERK1/2 signaling by PTHrP. Thus, CCN2 may be a new molecular target for anti-osteolytic therapy to shut off the PTHrP-CCN2 signaling pathway.

CCN3 Impairs Osteoblast and Stimulates Osteoclast Differentiation to Favor Breast Cancer Metastasis to Bone

“…50 -52 Whereas some studies suggest that CCN2/ CTGF is underexpressed in breast tumors relative to normal tissue, 51 others demonstrate that high CCN2/CTGF levels are critical for the bone metastatic phenotype of breast cancer cells. 53,54 Several studies have also examined the relationship between CCN3 levels and clinical outcome in patients with breast cancer. One study found no correlation between CCN3 mRNA levels and clinical outcome.…”

Role of Connective Tissue Growth Factor (CTGF/CCN2) in Oral Squamous Cell Carcinoma-Induced Bone Destruction

“…Neutralizing antibodies against CCN2 significantly inhibit local tumor growth, angiogenesis, and osteolysis caused by metastatic human breast cancer cells (Shimo T, et al, 2006). CCN2 and PTHrP are strongly expressed in cancer cells that have invaded the bone matrix, and CCN2 expression is regulated by PTHrP through PKA, PKC, and ERK1/2 MAPK pathways (Shimo T, et al, 2006). Furthermore, the CCN2 gene is significantly overexpressed in overt metastatic tumor cells as compared with its expression in disseminated tumor cells in the bone marrow of breast cancer patients by CT-guided bone metastasis biopsy and bone marrow biopsy (Cawthorn, et al, 2009).…”

“…It should be noted that CCN2 is one of the contributors to bone metastasis, as it converts low-metastatic breast cancer cells to high-metastatic ones in collaboration with other factors (Kang Y, et al, 2003;Minn AJ, et al, 2005). Neutralizing antibodies against CCN2 significantly inhibit local tumor growth, angiogenesis, and osteolysis caused by metastatic human breast cancer cells (Shimo T, et al, 2006). CCN2 and PTHrP are strongly expressed in cancer cells that have invaded the bone matrix, and CCN2 expression is regulated by PTHrP through PKA, PKC, and ERK1/2 MAPK pathways (Shimo T, et al, 2006).…”

“…Takayama, et al, 2010). Type I PTH/PTHrP receptor (PTH1R) expression is specifically observed in cancer cells producing PTHrP and CCN2 that have invaded the bone marrow, and PTHrP strongly up-regulates CCN2 in MDA-MB-231 cells in vitro (Shimo T, et al, 2006). CCN2 is also critically involved in osteolytic metastasis and is induced by PKA-and PKC-dependent activation of ERK 1/2 signaling by PTHrP (Shimo T, et al, 2006).…”

“…TGF- is one of the most potent inducers of CCN2, promoting CCN2 expression in bone metastatic cancer cells (Kang Y, et al, 2003); and the induction occurs through a complex network of transcriptional interactions requiring Smads, protein kinase C, and ras/MEK/ERK, as well as an Ets-1/transcription enhancer factor-binding element in the CCN2 promoter Leask A, et al, 2002;Van Beek JP, et al, 2006). TGFreleased from the bone causes a further increase in the expression of the TGF--responsive osteoclast-inducing genes, CCN2, RANKL, and TNF-in oral squamous cell carcinoma cells, thus establishing a composite positive-feedback cycle of metastasis (Kang Y, et al, 2003;Shimo T, et al, 2006).…”