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.
Highlights
Several studies have demonstrated that sites of chronic inflammation are often associated with the establishment and growth of various malignancies
This study is a sequel of our previous study and our data corroborates a novel link between arthritis induced inflammation and secondary metastasis associated with breast cancer
The survival of the PyV MT mice was significantly diminished with collagen-induced arthritis where all arthritic mice had to be euthanized by 149 days (~ 21 weeks) due to high tumor burden, ulceration of tumor, sluggish motion, hunched back and interferences with normal ambulation compared to 170+days (~24-25 weeks) for PyV MT mice without arthritis (P < 0.001)(Figure 1A)
Summary
Several studies have demonstrated that sites of chronic inflammation are often associated with the establishment and growth of various malignancies. 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. Both diseases are extremely prevalent in older post-menopausal women. We hypothesize that the proinflammatory microenvironment within the bone and lung caused by certain inflammatory conditions may partly account for the high prevalence of secondary metastasis to those organs. One such common inflammatory condition in humans is autoimmune arthritis (AA) which results in inflammation and deformity of the joints. Patients with non-Hodgkin’s lymphoma, skin cancer, and BC have significantly lower survival if they suffer from RA compared to their non-arthritic counterparts [3,4,5,6,7,8]
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