Targeting Src signaling in metastatic bone disease

Abstract

Src is a tyrosine kinase involved in the regulation of a range of cellular processes including proliferation, adhesion, motility and survival. In addition, it is a key regulator of bone metabolism. Src has been implicated in the pathogenesis of a number of cancers, and has been found to be overexpressed in breast, prostate, colorectal, pancreatic and nonsmall-cell lung tumors. There is also evidence that aberrant Src signaling may contribute to the increased osteoclastic activity associated with bone metastases. Bone metastases frequently occur in cancer patients with advanced disease. The metastasized cells disrupt normal bone remodeling pathways resulting in the release of growth factors that further promote tumor growth. Thus, a cycle of metastatic bone destruction is initiated, leading to compromised skeletal integrity and substantially reduced quality of life. Because of the role of Src in both cancer development and in bone metabolism, it may provide a therapeutic target for patients with bone metastases. ' 2008 Wiley-Liss, Inc.Key words: Src signaling; tyrosine kinase; bone metastases; osteoclasts Bone involvement in advanced cancerBone metastases are common in several cancers, including breast, prostate, colorectal and lung cancer. In addition, nearly all patients with multiple myeloma experience bone lesions. 1 Although bone resorption by osteoclasts and synthesis of new bone by osteoblasts is tightly regulated in normal bone metabolism, malignant cells dysregulate the bone remodeling process. The chronic presence of bone metastases often results in complete pathologic remodeling of the affected bone compartment.If untreated, bone metastases lead to skeletal complications such as fractures, spinal cord compression and bone pain, all of which may profoundly reduce patients' quality of life. Therefore, early diagnosis and adequate treatment of bone metastases is critically important.Cancer patients are also at risk of bone loss as a result of certain cancer therapies. In premenopausal women, chemotherapy can cause ovarian failure, leading to early menopause and rapid bone loss. 2 Adjuvant endocrine therapies that deplete peripheral sex hormone production can also reduce bone mass. Bone loss is also frequently seen in men receiving androgen-deprivation therapy for prostate cancer, leading to an increased risk of osteoporotic fracture. 3 Molecular biology of Src family kinasesSrc (encoded by the c-src gene) is a nonreceptor tyrosine kinase localized to the cellular membrane, involved in the regulation of a range of cellular processes, including proliferation, adhesion, motility and survival (for a review see Yeatman or Rucci et al. 4,5 ). It is the best-characterized member of the Src family kinases (SFKs), a family of 9 similar proteins that also includes Blk, Fgr, Fyn, Hck, Lck, Lyn, Yes and Yrk. 4,5 SFK members share a unique domain and 3 other domains termed the kinase domain and Src homology (SH) domains SH2 and SH3. The kinase domain phosphorylates tyrosine residues in substrates that bind to the SH...

C-Src-mediated RANKL-induced breast cancer cell migration by activation of the ERK and Akt pathway

“…This antibody had been fast tracked by the US FDA for treatment and prevention of post-menopausal osteoporosis and treatment and prevention of bone loss in hormone-treated prostate and breast cancer patients (34,35). Furthermore, Src inhibitors, including dasatinib, saracatinib and bosutinib, are currently under clinical investigation for patients with solid tumors, as available data show activity in bone (36)(37)(38)(39). Our results have shown the direct anti-metastasis effects of RANKL and/or c-Src inhibitors.…”

SKI-606 (Bosutinib) Blocks Prostate Cancer Invasion, Growth, and Metastasis In vitro and In vivo through Regulation of Genes Involved in Cancer Growth and Skeletal Metastasis

“…Targeted knock out of Src in mice results in osteopetrosis, whereas bone-specific expression of Src in these mice rescues normal osteoclast function (7). Because Src plays a pivotal role in tumor progression and bone turnover, its signaling is of particular significance in the development and progression of skeletal metastases associated with several cancers (8).…”

Cell surface heat shock protein 90 modulates prostate cancer cell adhesion and invasion through the integrin-β1/focal adhesion kinase/c-Src signaling pathway

“…β1 with FAK and c-Src. the ecM-dependent dynamic assembly of focal adhesion molecules, including the Fn-induced association of integrin β1 with c-src or FAK, plays a key role in cell migration (13)(14)(15). In many signaling contexts, this complex acts to control the turnover of focal cell adhesions during cell migration.…”

“…the signals initiated by ecM-integrin interactions are transduced into cells through multiple intracellular signaling pathways, including a cascade of tyrosine phosphorylation events. two important mediators of this process are focal adhesion kinase (FAK) (14) and src (15), two non-receptor tyrosine kinases. clustering of the integrins facilitates the autophosphorylation of tyrosine 397, which increases the catalytic activity of FAK.…”

“…In prostate cancer cells, the FAK/src signaling pathway and some of its downstream targets (including p130cas and paxillin) have been proposed to be involved in regulating integrins-mediated cell migration and invasion (13)(14)(15)(16)(17)(18)(19)(20). High levels of FAK/src expression and signaling have been shown to be positively correlated with the invasive and migratory capacity of prostate cancer cells (13)(14)(15)(16)(17)(18)20). therefore, it has been proposed that cell surface Hsp90 likely modulates pc3 cell motility by mediating integrin-FAK/src signaling.…”