Markers of bone turnover (ICTP, NTX) and serum matrix metalloproteinase 1 (MMP1) as prognostic markers in breast cancer patients (BC) with bone metastases (BM) treated with bisphosphonates (BP)

Costa, Luís; Alho, Irina; Casimiro, Sandra; Oliveira, Anjolina Grisi de; Luis, Ines Maria Vaz Duarte; Fernandes, Afonso; Bicho, Manuel; Ali, Simak; Leitzel, Kim; Demers, Laurence M.; Lipton, Allan

doi:10.1200/jco.2008.26.15_suppl.1024

Cited by 5 publications

(3 citation statements)

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“…In fact osteoclasts do not express MMP-1 [40]. In a study with breast cancer patients with bone metastasis we showed that ICTP and MMP-1 baseline levels were associated with a shorter time to development of skeletal-related events, suggesting that MMP-1 might be useful to detect patients with tumor-induced osteolysis [41]. More recently, in a study with 92 patients with bone metastasis from solid tumors, we demonstrated that MMP-1 was expressed in most cases, independently of tumor type, X-ray pattern of bone lesions, and previous bisphosphonate therapy.…”

Section: Discussionmentioning

confidence: 90%

RANKL/RANK/MMP-1 Molecular Triad Contributes to the Metastatic Phenotype of Breast and Prostate Cancer Cells In Vitro

Casimiro¹,

Mohammad

Pires³

et al. 2013

PLoS ONE

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The osteolytic nature of bone metastasis results from a tumor-driven increased bone resorption. Bone remodeling is orchestrated by the molecular triad RANK-RANKL-OPG. This process is dysregulated in bone metastases, mostly via induction of RANKL by tumor-derived factors. These factors increase expression of RANKL, which induce osteoclast formation, function, and survival, thereby increasing bone resorption. RANK is unexpectedly expressed by cancer cells, and the activation of RANKL-RANK pathway correlates with an increased invasive phenotype. To investigate the interaction between RANK expression in human breast and prostate cancer cells and their pro-metastatic phenotype we analyzed the activation of RANKL-RANK pathway and its effects on cell migration, invasion, gene expression in vitro, and osteolysis-inducing ability in vivo. RANKL activates kinase signaling pathways, stimulates cell migration, increases cell invasion, and up-regulates MMP-1 expression. In vivo, MMP-1 knockdown resulted in smaller x-ray osteolytic lesions and osteoclastogenesis, and decreased tumor burden. Therefore, RANKL inhibition in bone metastatic disease may decrease the levels of the osteoclastogenesis inducer MMP-1, contributing to a better clinical outcome.

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Section: Discussionmentioning

confidence: 90%

RANKL/RANK/MMP-1 Molecular Triad Contributes to the Metastatic Phenotype of Breast and Prostate Cancer Cells In Vitro

Casimiro¹,

Mohammad

Pires³

et al. 2013

PLoS ONE

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Section: Mmps In Bone Cancer and Bone Metastasesmentioning

confidence: 99%

“…Increased MMP-9 activity correlated with osteoclast activity in a PC-3 prostate cancer model of osteolytic bone metastases. In a prospective study with 71 breast cancer patients with bone metastases, Costa et al (2008) showed that serum ICTP (C-terminal telopeptide, generated by MMP-1 cleavage of type I collagen) and MMP-1 concentrations were associated with a shorter time to development of skeletal-related events.Despite these convincing associations with MMPs and metastasis, the results of MMP inhibitor phase III clinical trials of generalized metastases have been disappointing (Coussens et al 2002). One possibility for this failure could be that the studies were designed to measure outcomes of generalized metastases.…”

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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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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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Functional protease profiling for diagnosis of malignant disease

Findeisen

Neumaier

2011

Proteomics Clinical Apps

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Clinical proteomic profiling by mass spectrometry (MS) aims at uncovering specific alterations within mass profiles of clinical specimens that are of diagnostic value for the detection and classification of various diseases including cancer. However, despite substantial progress in the field, the clinical proteomic profiling approaches have not matured into routine diagnostic applications so far. Their limitations are mainly related to high-abundance proteins and their complex processing by a multitude of endogenous proteases thus making rigorous standardization difficult. MS is biased towards the detection of low-molecular-weight peptides. Specifically, in serum specimens, the particular fragments of proteolytically degraded proteins are amenable to MS analysis. Proteases are known to be involved in tumour progression and tumour-specific proteases are released into the blood stream presumably as a result of invasive progression and metastasis. Thus, the determination of protease activity in clinical specimens from patients with malignant disease can offer diagnostic and also therapeutic options. The identification of specific substrates for tumour proteases in complex biological samples is challenging, but proteomic screens for proteases/substrate interactions are currently experiencing impressive progress. Such proteomic screens include peptide-based libraries, differential isotope labelling in combination with MS, quantitative degradomic analysis of proteolytically generated neo-N-termini, monitoring the degradation of exogenous reporter peptides with MS, and activity-based protein profiling. In the present article, we summarize and discuss the current status of proteomic techniques to identify tumour-specific protease-substrate interactions for functional protease profiling. Thereby, we focus on the potential diagnostic use of the respective approaches.

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Markers of bone turnover (ICTP, NTX) and serum matrix metalloproteinase 1 (MMP1) as prognostic markers in breast cancer patients (BC) with bone metastases (BM) treated with bisphosphonates (BP)

Cited by 5 publications

References 0 publications

RANKL/RANK/MMP-1 Molecular Triad Contributes to the Metastatic Phenotype of Breast and Prostate Cancer Cells In Vitro

RANKL/RANK/MMP-1 Molecular Triad Contributes to the Metastatic Phenotype of Breast and Prostate Cancer Cells In Vitro

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

Functional protease profiling for diagnosis of malignant disease

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