Matrix Metalloproteinase Activity, Bone Matrix Turnover, and Tumor Cell Proliferation in Prostate Cancer Bone Metastasis

Nemeth, Jeffrey A.; Yousif, Rafid; Herzog, M.; Che, Mingxin; Upadhyay, Jyoti; Shekarriz, Bijan; Bhagat, Sunita; Mullins, Chadwick; Fridman, Rafael; Cher, Michael L.

doi:10.1093/jnci/94.1.17

Cited by 207 publications

(169 citation statements)

References 40 publications

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“…MMPs are increased in most cancers, including breast and prostate (Upadhyay et al 1999;Bachmeier et al 2001;Nemeth et al 2002), and high levels of MMPs have been associated with poor prognosis (John and Tuszynski 2001;Nakopoulou et al 2002Nakopoulou et al , 2003Ranuncolo et al 2003). In an animal model of prostate cancer osteolytic bone metastasis, MMP-7-deficient mice had less osteolysis due to defective RANKL processing and reduced osteoclast activation (Lynch et al 2005).…”

Section: Mmps In Bone Cancer and Bone Metastasesmentioning

confidence: 99%

“…Several MMPs expressed in bone function in endochondral ossification during embryonic development and in modeling and remodeling of bone postnatally and later in life (Krane and Inada 2008). In support of the latter, mice homozygous for a targeted mutation in Col1a1 that are resistant to collagenase cleavage of type I collagen are resistant to PTH-induced osteoclastic bone resorption (Zhao et al 2000).MMPs are increased in most cancers, including breast and prostate (Upadhyay et al 1999;Bachmeier et al 2001;Nemeth et al 2002), and high levels of MMPs have been associated with poor prognosis (John and Tuszynski 2001;Nakopoulou et al 2002Nakopoulou et al , 2003Ranuncolo et al 2003). In an animal model of prostate cancer osteolytic bone metastasis, MMP-7-deficient mice had less osteolysis due to defective RANKL processing and reduced osteoclast activation (Lynch et al 2005).…”

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Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

Guise

2009

Genes Dev.

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Bone metastases are the most common skeletal complication of malignancy. Tumor cells disrupt normal bone remodeling to promote bone destruction and its associated morbidity. In the August 15, 2009, issue of Genes & Development, Lu and colleagues (pp. 1882-1894) propose a novel molecular mechanism by which tumor-produced metalloproteinases release epidermal growth factor (EGF) ligands to activate the central osteoclastogenic pathway receptor activator of NF-kB ligand (RANKL) to promote breast cancer osteolysis. This work has important therapeutic applications that may quickly translate to more effective treatment for bone metastases.Bone metastases are common in breast, prostate, and lung cancer, and are associated with significant morbidity. Unique aspects of the bone microenvironment-such as mineralized bone matrix, which houses immobilized growth factors, bone-destroying osteoclasts, and boneforming osteoblasts-make it a fertile soil for these cancers to grow. Significant insight into the molecular mechanisms responsible for the proclivity of tumors to metastasize and grow in bone has been gleaned in recent years from mouse models and clinical studies. Bone destruction mediated by solid tumor metastases to bone, particularly in breast cancer, is driven by tumor stimulation of osteoclastic bone resorption. Collective evidence supports the notion that effective therapy for bone metastases should target both the tumor and the bone microenvironment. Indeed, bisphosphonate therapy to block osteoclastic bone resorption, used in conjunction with standard anti-cancer treatments, reduces bone pain, pathologic fracture, and hypercalcemia associated with bone metastases from all tumor types. However, regression and cure of bone metastases have yet to be achieved with the current therapeutic armamentarium. Thus, a better understanding of the molecular mechanisms responsible for this devastating skeletal complication of malignancy is required to develop more effective therapy, with the eventual goal of curing and preventing bone metastases. In the August 15, 2009, issue of Genes & Development, Lu et al. (2009) bring the field closer to this goal. They describe an autocrine/paracrine signaling cascade triggered by metalloproteinases-matrix metalloproteinase-1 (MMP-1) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1)-and cleavage of epidermal growth factor (EGF) ligands to reduce the ratio of osteoblast-produced receptor activator of NF-kB ligand (RANKL) to osteoprotegerin (OPG) to favor osteoclastogenesis and promote breast cancer osteolysis. These studies, described herein, have important implications for new applications of standard cancer therapy that could result in more effective treatment for bone metastases. Bone metastases: clinical features and current therapyCertain solid tumors-such as breast, prostate, and lung cancer-have a propensity to metastasize to bone to cause bone pain, fracture, hypercalcemia, and paralysis. This morbidity is great: Up to 75% of advanced breast and prostate c...

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Section: Mmps In Bone Cancer and Bone Metastasesmentioning

confidence: 99%

mentioning

confidence: 99%

Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

Guise

2009

Genes Dev.

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“…MMP-9 and MMP-2 have been shown to be capable of cleaving latent TGF-β and activating it [67]. In support of the idea that TGF-β activated by MMPs is key to continuation of the vicious cycle is the finding that MMP inhibition disrupts bone matrix turnover and tumor growth [57]. The release of sequestered TGF-â with subsequent activation thus represents a potentially vital mechanism for enhanced tumor growth.…”

Section: Microenvironment Of Bone Metastasesmentioning

confidence: 99%

Proteases as modulators of tumor–stromal interaction: Primary tumors to bone metastases

Wilson

Singh

2008

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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SummaryAs cells undergo oncogenic transformation and as transformed cells arrive at metastatic sites, a complex interplay occurs with the surrounding stroma. This dialogue between tumor and stroma ultimately dictates the success of the tumor cells in the given microenvironment. As a result, understanding the molecular mechanisms at work is important for developing new therapeutic modalities. Proteases are major players in the interaction between tumor and stroma. This review will focus on the role of proteases in modulating tumor-stromal interactions of both primary breast and prostate tumors as well as at bone metastatic sites in a way that favors tumor growth.

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“…Gelatinases (MMP-2 and -9) have been found to be associated with prostate cancer metastasis. For example, Nemeth et al 31 have shown higher expression of gelatinases by prostate cancer cells when growing in bone; interestingly, CXCL12 is largely expressed by bone marrow. 32 High MMP-2 and -9 levels in plasma also correlate with prostate cancer metastasis.…”

Section: Cxcr4-mediated Pca Migration and Invasionmentioning

confidence: 99%

CXCL12–CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion

Singh

Grizzle

et al. 2004

Laboratory Investigation

213

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The mechanisms responsible for prostate cancer metastasis are incompletely understood at both the cellular and molecular levels. In this regard, chemokines are a family of small, cytokine-like proteins that induce motility of neoplastic cells, leukocytes and cancer cells. The current study evaluates the molecular mechanisms of CXCL12 and CXCR4 in prostate cancer cell migration and invasion. We report that functional CXCR4 is significantly expressed by prostate cancer cell lines, LNCaP and PC3, when compared with normal prostatic epithelial cells (PrEC). As measured using motility and invasion chamber assays, prostate cancer cells migrated and invaded through extracellular matrix components in response to CXCL12, at rates that corresponded to CXCR4 expression. Anti-CXCR4 antibodies (Abs) significantly impaired the migration and invasive potential of PC3 and LNCaP cells. CXCL12 induction also enhanced collagenase-1 (metalloproteinase-1 (MMP-1)) expression by LNCaP and PC3 cells. Collagenase-3 (MMP-13) was expressed by prostate cancer cells, but it was not expressed by PrEC cells or modulated by CXCL12. CXCL12 increased MMP-2 expression by LNCaP and PC3; however, MMP-9 expression was elevated only in PC3 cells after CXCL12-CXCR4 ligation. PC3 cells also expressed high levels of stromelysin-1 (MMP-3) after CXCL12 stimulation. CXCL12 also significantly Keywords: chemokine; metastasis; metalloproteinase; stromal cell-derived factor-1; SDF-1 Despite the obvious importance of metastasis, this process remains incompletely understood at both the cellular and molecular levels. 1 Many factors have been implicated in the process of metastasis, but the precise mechanisms for the directional migration of malignant cells into different organs is unknown. [2][3][4] In this regard, chemokines are a super family of small, cytokine-like proteins that inducethrough G-protein-coupled receptor and cytoskeletal rearrangement-the adhesion of neoplastic cells or leukocytes to endothelial cells as well as the directional migration of cancer cells. 5,6 The ability of neoplastic cells to penetrate the basement membrane and then invade the interstitial stroma to initiate the metastatic process is largely mediated by proteolysis. Many proteinases are capable of degrading extracellular matrix (ECM) components, but matrix metalloproteinases (MMPs) appear to be particularly important for matrix degradation. 6 These proteolytic enzymes are involved in connective tissue remodeling as well as in embryonic growth, ovulation, wound healing and menstruation. 7,8 Moreover, abnormal production of these proteinases is implicated in a number of pathological conditions. 9 It has been shown that CXCL12-CXCR4 interactions may play a role in the metastasis of prostate cancer to bone. 10 However, these interactions alone do not explain the metastasis pattern of prostate cancer or the potential for neoplastic prostate cells to migrate and invade other tissues. We have tested the hypothesis that prostate carcinomas use CXCR4-

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Matrix Metalloproteinase Activity, Bone Matrix Turnover, and Tumor Cell Proliferation in Prostate Cancer Bone Metastasis

Abstract: MMP activity appears to play an important role in bone matrix turnover when prostate cancer cells are present in bone. Bone matrix turnover and metastatic tumor growth appear to be involved in a mutually supportive cycle that is disrupted by MMP inhibition.

Cited by 207 publications

References 40 publications

Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

Proteases as modulators of tumor–stromal interaction: Primary tumors to bone metastases

CXCL12–CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion

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