Mechanisms of cancer metastasis to the bone

Yin, Juan Juan; Pollock, Claire B.; Kelly, Kathleen

doi:10.1038/sj.cr.7290266

Cited by 307 publications

(244 citation statements)

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“…However, Otto et al have also documented expression of the Runx2 gene in the nascent mammary epithelium of mice in vivo, suggesting that Runx2 has a role in the mammary gland . Furthermore, it is well established that breast cancers preferentially metastasise to the bone and that they express ''bone genes'' [Martin and Gillespie, 2001;Yin et al, 2005;Yoneda and Hiraga, 2005]. From the above observations it is reasonable to hypothesize that Runx2 regulates gene expression in the mammary epithelium and that the Runx2 genetic program somehow contributes to the ability of cancerous mammary epithelial cells to metastasise to the bone.…”

Section: Runx2 Expression In Mammary Epithelial Cellsmentioning

confidence: 98%

“…For example, genes important in the control of bone remodelling are expressed in breast cancer and lactating breast, such as RANK, RANKL, vitamin D, bone sialoprotein (BSP), osteopontin (OPN), and calcitonin [Martin and Gillespie, 2001]. In addition, breast cancers preferentially metastasise to the bone [Yin et al, 2005;Yoneda and Hiraga, 2005]. Breast cancer cells that establish themselves in the bone are thought to modulate, either directly or indirectly, the activity of osteogenic cells, resulting in local bone degradation.…”

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confidence: 99%

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A role for Runx2 in normal mammary gland and breast cancer bone metastasis

Shore

2005

J of Cellular Biochemistry

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The transcription factor Runx2 is essential for the formation of the skeleton. It has therefore primarily been considered as a specific regulator of bone genes. However, mice containing a LacZ insertion at the Runx2 locus also revealed expression in the nascent mammary epithelium. Reports of Runx2 expression in breast cancer cell lines, combined with the fact that breast cancers preferentially metastasise to bone, have also hinted at a potential role for Runx2 in the formation of bone metastasese. These initial observations have prompted further analysis of Runx2 function in mammary epithelial cells and recent findings have demonstrated that Runx2 does indeed contribute to the ability of metastatic breast cancer cell lines to form osteolytic bone lesions. In addition, evidence is accumulating that Runx2 has a role in the regulation of normal mammary gland gene expression and recent data demonstrate that it regulates transcription of the mammary gland-specific gene, b-casein. In this article I discuss recent advances that link Runx2 with normal mammary epithelial cell function and the development of bone metastasese in breast cancer.

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Section: Runx2 Expression In Mammary Epithelial Cellsmentioning

confidence: 98%

mentioning

confidence: 99%

A role for Runx2 in normal mammary gland and breast cancer bone metastasis

Shore

2005

J of Cellular Biochemistry

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“…The detection of bone metastases relies on imaging technology, but novel approaches based on biomarker assessments are under intense investigation. Increasing body of data suggests that metastatic dissemination is site specific (Horak and Steeg, 2005) and that distinct molecular factors regulate bone metastasis formation (Yin et al, 2005). A multifactorial and multistep process of bone metastasis formation involves several biological mechanisms including angiogenesis, invasion through extracellular matrix degradation, osteoblast/ osteoclast activation and bone remodeling activity (Guise and Mundy 1998).…”

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confidence: 99%

“…High circulating levels of VEGF have been found to correlate with more advanced stages or with a worse prognosis in different tumours and in particular in women with breast cancer (Linderholm et al, 2000). Histological studies of bone metastases show that tumour cells remain in the bone marrow cavity and secrete factors that regulate bone cells including parathyroid hormone related protein (PTHrP), tumour necrosis factor (TNF), interleukin-6 (IL-6) and transforming growth factor (TGF)b (Yin et al, 2005). Among these local factors, serum TGFb was recently shown to be associated with disease progression and poor prognosis in patients with metastatic breast cancer (Cui et al, 1996;Sheen-Chen et al 2001;Ivanovic et al, 2003).…”

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confidence: 99%

Association of 12 serum biochemical markers of angiogenesis, tumour invasion and bone turnover with bone metastases from breast cancer: a crossectional and longitudinal evaluation

Voorzanger-Rousselot¹,

Juillet²,

Mareau³

et al. 2006

Br J Cancer

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Complex biological pathways including angiogenesis, invasion, osteoclastic activation and bone matrix degradation are involved in the formation of bone metastasis (BM). The aim of our study was to investigate the cross-sectional and longitudinal associations of a panel of 12 serum biochemical markers reflecting biological pathways underlying BM development. In a cross-sectional study, we investigated 29 patients with primary breast carcinoma without BM (BC/BMÀ), 28 patients with breast carcinoma and BM (BC/ BM þ ) and 15 healthy women. In longitudinal analyses, we investigated 34 patients for whom serum was obtained a two different time points: at the time of primary BC diagnosis and after a median time of 3 years. During this follow-up, 15 patients developed BM, whereas the other 19 remained free of BM. In patients who developed BM, the second samples were obtained before BM was documented by bone scan. The cross-sectional analyses have shown all biochemical markers to be significantly elevated in patients with BM, when compared to the patients without BM and healthy controls, except TGFb1 that was significantly decreased. Multivariable analyses showed that only the bone resorption markers TRACP 5b, CTX and ICTP, and the marker of angiogenesis VEGF were independently associated with BM. Those markers correctly distinguished 85% of BC patients with or without BM from normal individuals. Longitudinal analyses showed that patients with primary BC who developed BM during follow-up had higher levels of TRACP5b ( þ 95%, P ¼ 0.08) at the time of primary diagnosis, those patients had also a higher increases of ICTP (P ¼ 0.006), MMP-7 (P ¼ 0.004) and TIMP-1 (P ¼ 0.017) during follow-up than patients who did not progress toward bone metastasis. This study provides evidence of increase and interrelationship of circulating markers of angiogenesis, invasion and bone resorption in patients with BC with and without BM. Markers of bone resorption have the highest independent diagnostic value for detecting and potentially predicting BM in breast carcinoma patients. Bone is one of the most common sites of metastasis for certain types of tumours, especially prostate, breast and lung carcinoma (Mundy, 2002). Breast cancer progression to bone is a defining feature of a highly malignant tumour and the major cause of cancer-treatment failure. Early detection of bone metastasis is critical for clinical management and accurate staging of tumours. Currently there is no a simple way to reliably detect and predict which patients will develop bone metastasis. The detection of bone metastases relies on imaging technology, but novel approaches based on biomarker assessments are under intense investigation. Increasing body of data suggests that metastatic dissemination is site specific (Horak and Steeg, 2005) and that distinct molecular factors regulate bone metastasis formation (Yin et al, 2005). A multifactorial and multistep process of bone metastasis formation involves several biological mechanisms including angiogenesis, invasion through...

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“…1 Breast and prostate cancer account for approximately 80% of cases of bone blastic metastases. 2, 3 Osteoblastic metastases originating from tumors of prostate or breast may be involved in new bone formation given that they stimulate osteoblasts to produce collagen, osteocalcin, and alkaline phosphatases. Thus, the typical radiological imaging appears as an area of increased bone deposition.…”

Section: Introductionmentioning

confidence: 99%

A Complementary Method for the Detection of Osteoblastic Metastases on Digitized Radiographs

González-Sistal

Sánchez

2006

J Digit Imaging

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Purpose: This study was conducted to evaluate the diagnostic usefulness of gray level parameters in order to distinguish healthy bone from osteoblastic metastases on digitized radiographs. Materials and methods: Skeletal radiographs of healthy bone (n = 144) and osteoblastic metastases (n = 35) were digitized using pixels 0.175 mm in size and 4,096 gray levels. We obtained an optimized healthy bone classification to compare with pathological bone: cortical, trabecular, and flat bone. The osteoblastic metastases (OM) were classified in nonflat and flat bone. These radiological images were analyzed by using a computerized method. The parameters (gray scale) calculated were: mean, standard deviation, and coefficient of variation (MGL, SDGL, and CVGL, respectively) based on gray level histogram analysis. Diagnostic utility was quantified by measurement of parameters on healthy and pathological bone, yielding quantification of area under the receiver operating characteristic (ROC) curve, AUC. Results: All three image parameters showed high and significant values of AUC when comparing healthy trabecular bone and nonflat bone OM, showing MGL the best discriminatory ability (0.97). As for flat bones, MGL showed no ability to distinguish between healthy and flat bone OM (0.50). This could be achieved by using SDGL or CVGL, with both showing a similar diagnostic ability (0.85 and 0.83, respectively). Conclusion: Our results show that the use of gray level parameters quantify healthy bone and osteoblastic metastases zones on digitized radiographs. This may be helpful as a complementary method for differential diagnosis. Moreover, our method will allow us to study the evolution of osteoblastic metastases under medical treatment.

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Mechanisms of cancer metastasis to the bone

Cited by 307 publications

References 42 publications

A role for Runx2 in normal mammary gland and breast cancer bone metastasis

A role for Runx2 in normal mammary gland and breast cancer bone metastasis

Association of 12 serum biochemical markers of angiogenesis, tumour invasion and bone turnover with bone metastases from breast cancer: a crossectional and longitudinal evaluation

A Complementary Method for the Detection of Osteoblastic Metastases on Digitized Radiographs

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