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

Abstract

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.

Lysophosphatidic acid production and action: critical new players in breast cancer initiation and progression

“…Systemic inflammation has been associated with an increased risk of breast cancer development (Gadalla et al, 2009) and metastasis (Das Roy et al, 2009). In addition, local inflammation leading to chronic mastitis in the mammary gland occurred at a higher frequency and earlier time point of tumour development in the ATX and LPA receptor transgenic mice .…”

Systemic inflammation promotes lung metastasis via E-selectin upregulation in mouse breast cancer model

“…[14][15][16] A previous study has shown that the incidence of breast cancer associated lung metastasis is significantly higher in mice with arthritis. 17 Moreover, celecoxib, an anti-inflammation drug, significantly reduces metastasis to lungs. 18,19 These findings indicate the correlation between inflammatory microenviroment and the homing of circulating tumor cells.…”

Celecoxib/PLGA Suprime Angiogénesis y Metástasis Pulmonar de un Cáncer Mamario Murino Experimental

“…Si bien Cx ha sido previamente reportado su acción frente a metástasis pulmonar (Gendy et al, 2011;Barlow et al, 2012;Zhang et al, 2014) y hueso (Das Roy et al, 2009), y frente a apoptosis y crecimiento tumoral en el mismo modelo (Rosas et al, 2014); no hay información de su efecto frente a metástasis pulmonar cuando es asociado a micropartículas de PLGA.…”