Elevated serum M-CSF level predicts reduced survival in metastatic breast cancer patients

Leitzel, Kim; Ettenberg, Seth A.; Walsh, Robert J.; Abraham, Jim; Modur, Vishnu; Braendle, Edgar; Evans, Dean B.; Ali, Suhail M.; Demers, Lawrence M.; Lipton, Allan

doi:10.1200/jco.2007.25.18_suppl.10591

Cited by 5 publications

(4 citation statements)

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“…In fact, elevated serum M-CSF predicts reduced survival in metastatic breast cancer patients [ 37 ]. At the same time, the M-CSF produced by breast cancer cells and surrounding stroma increases osteoclast formation and maturation and enhances the expression of stromal RANK ligand, both of which increase osteolytic bone degradation [ 38 ]. M-CSF also contributes to the pathogenesis of RA through up regulation of neutrophil gelatinase-associated lipocalin (NGAL) in neutrophils, followed by induction of transitional endoplasmic reticulum ATPase (TERA), cathepsin D and transglutaminase 2(TG2) in synoviocytes [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer

et al. 2011

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BackgroundSeveral studies have demonstrated that sites of chronic inflammation are often associated with the establishment and growth of various malignancies. A common inflammatory condition in humans is autoimmune arthritis (AA). Although AA and cancer are different diseases, many of the underlying processes that contribute to the disorders of the joints and connective tissue that characterize AA also affect cancer progression and metastasis. Systemically, AA can lead to cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge being available, there has been minimal research linking breast cancer, arthritis, and metastasis associated with breast cancer. Notably both diseases are extremely prevalent in older post-menopausal women.MethodsTo establish the novel link between arthritis induced inflammation and secondary metastasis associated with breast cancer, PyV MT mice that spontaneously develop mammary gland carcinoma were injected with Type II collagen (CII) to induce arthritis at 9 and 18 weeks of age for pre-metastatic and metastatic condition. The sites of secondary metastasis and the associated inflammatory microenvironment were evaluated.ResultsA significant increase in breast cancer-associated secondary metastasis to the lungs and bones was observed in the arthritic versus the non-arthritic PyV MT mice along with an increase in primary tumor burden. We report significant increases in the levels of interstitial cellular infiltrates and pro-inflammatory cytokines such as interleukin-17 (IL-17), interleukin-6 (IL-6), Pro- Matrix metallopeptidase 9 (Pro-MMP9), insulin like growth factor-II (GF-II) and macrophage colony stimulating factor (M-CSF) in the arthritic lung and bone milieu as well as in the circulation. These pro-inflammatory cytokines along with the inflammatory microenvironment may be the underlying factors facilitating tumor progression and metastasis in arthritic PyV MT mice. This was further substantiated by treatment with celecoxib, an anti-inflammatory drug + αIL-17 antibody that significantly reduced the secondary metastasis to lung and bone.ConclusionsThe data generated not only reveal the underlying mechanism of high susceptibility to bone and lung metastasis in an arthritic condition but our combination therapies may lead to treatment modalities that will be capable of reducing tumor burden, and preventing relapse and metastasis in arthritic patients with breast cancer.

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Section: Discussionmentioning

confidence: 99%

Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer

et al. 2011

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“…Elevated serum M-CSF predicts reduced survival in metastatic breast cancer patients [ 32 , 33 ]. The M-CSF produced by breast cancer cells and surrounding stroma increases osteoclast formation and maturation and enhances the expression of stromal RANK ligand, both of which increase osteolytic bone degradation [ 34 ]. IL-17 has been identified as a crucial cytokine for osteoclastic bone resorption in AA patients [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Breast cancer-associated metastasis is significantly increased in a model of autoimmune arthritis

et al. 2009

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IntroductionSites of chronic inflammation are often associated with the establishment and growth of various malignancies including breast cancer. A common inflammatory condition in humans is autoimmune arthritis (AA) that causes inflammation and deformity of the joints. Other systemic effects associated with arthritis include increased cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge, available for a decade, it has never been questioned if the site of chronic inflammation linked to AA creates a milieu that attracts tumor cells to home and grow in the inflamed bones and lungs which are frequent sites of breast cancer metastasis.MethodsTo determine if chronic inflammation induced by autoimmune arthritis contributes to increased breast cancer-associated metastasis, we generated mammary gland tumors in SKG mice that were genetically prone to develop AA. Two breast cancer cell lines, one highly metastatic (4T1) and the other non-metastatic (TUBO) were used to generate the tumors in the mammary fat pad. Lung and bone metastasis and the associated inflammatory milieu were evaluated in the arthritic versus the non-arthritic mice.ResultsWe report a three-fold increase in lung metastasis and a significant increase in the incidence of bone metastasis in the pro-arthritic and arthritic mice compared to non-arthritic control mice. We also report that the metastatic breast cancer cells augment the severity of arthritis resulting in a vicious cycle that increases both bone destruction and metastasis. Enhanced neutrophilic and granulocytic infiltration in lungs and bone of the pro-arthritic and arthritic mice and subsequent increase in circulating levels of proinflammatory cytokines, such as macrophage colony stimulating factor (M-CSF), interleukin-17 (IL-17), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha (TNF-alpha) may contribute to the increased metastasis. Treatment with anti-IL17 + celecoxib, an anti-inflammatory drug completely abrogated the development of metastasis and significantly reduced the primary tumor burden.ConclusionsThe data clearly has important clinical implications for patients diagnosed with metastatic breast cancer, especially with regards to the prognosis and treatment options.

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“…Elevated serum M-CSF predicts reduced survival in metastatic breast cancer patients. The M-CSF produced by breast cancer cells and surrounding stoma increases osteoclast formation and maturation and enhances the expression of stromal RANK ligand, both of which increase osteolytic bone degradation 17 . IL-17 has been identified as a crucial cytokine for osteoclastic bone resorption in AA patients.…”

Section: Discussionmentioning

confidence: 99%

Breast Cancer Associated Metastasis is Significantly Increased in a Model of Autoimmune Arthritis

et al. 2008

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Chronic inflammation is known to play a role in cancer initiation, promotion, and metastasis. However, the mechanism by which inflammation promotes metastasis is still unclear. We evaluated if chronic inflammation induced by autoimmune arthritis may contribute to increased breast cancer-associated metastasis. We report a threefold increase in lung metastasis and a significant increase in the incidence of bone metastasis in the pro-arthritic mice compared to control mice. The metastatic breast tumors in turn augment the severity of arthritis resulting in a vicious cycle that increases both bone destruction and metastasis. Enhanced neutrophilic and granulocytic infiltration in lungs and bone of the pro-arthritic mice and subsequent increase in circulating levels of proinflammatory cytokines, such as IL-17, IL-6, VEGF, and TNF-α were the underlying factors contributing to the increased metastasis. The data clearly has important clinical implications for patients diagnosed with metastatic breast cancer.

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Elevated serum M-CSF level predicts reduced survival in metastatic breast cancer patients

Cited by 5 publications

References 0 publications

Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer

Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer

Breast cancer-associated metastasis is significantly increased in a model of autoimmune arthritis

Breast Cancer Associated Metastasis is Significantly Increased in a Model of Autoimmune Arthritis

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