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

Abstract

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.

Acute inflammation induced by the biopsy of mouse mammary tumors promotes the development of metastasis

“…A number clinical studies and mouse models have shown an association of chronic inflammatory diseases and risk of cancer and/or cancer progression [28]. In addition, more recent studies in mouse models have demonstrated that breast cancer-associated metastasis is significantly increased in models of autoimmune arthritis [7, 8]. …”

“…The association between chronic inflammation and cancer has been most evident in diseases such as ulcerative colitis, which carries a significantly elevated risk of colon cancer [5, 6]. Recent studies have shown that chronic arthritis in mice leads to an enhanced frequency of mammary tumors and metastasis [7, 8]. It is becoming evident through animal studies that selective types of immune responses and immune cells can promote tumor progression more than others.…”

The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis

“…A recent study suggests that these considerations are worth further exploration: in a mouse model of arthritis, the systemic inflammatory effects significantly increased breast-cancer-associated metastases to both lungs and bones in arthritic compared to non-arthritic mice 87 . The pre-metastatic lungs of arthritic mice were highly inflamed, and use of an anti-interleukin (IL)-17 antibody significantly reduced inflammation and metastatic burden in both lungs and bone.…”

Lymphocyte-derived interleukin-17A adds another brick in the wall of inflammation-induced breast carcinogenesis

“…The role of IL-17A in breast cancer has been suggested by studies in vitro 1 and further substantiated in animal models 4 , 5 and in clinical samples 5 , 6 . Furthermore, IL17R knockdown in 4T1 cells decreased cancer growth in vivo and, of particular surprise, induced cancer cell death 6 .…”

“…IL-17A neutralization also resulted in the drastic diminution of colon cancer cell growth and decreased the growth of ovarian and lung cancer cell lines. Of particular interest, IL-17A neutralizing antibodies reduced the tumor growth and metastasis of several mouse models of breast cancer 4 , 5 …”