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
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DOI：
10.1186/1471-2407-11-365
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发表时间：
2011-08-22
期刊：
影响因子：
3.8
通讯作者：
Mukherjee, Pinku
中科院分区：
文献类型：
--
作者：
Das Roy, Lopamudra;Ghosh, Sriparna;Mukherjee, Pinku
背景：多项研究表明，慢性炎症部位往往与各种恶性肿瘤的发生和发展有关。人类常见的炎症性疾病是自身免疫性关节炎(AA)。虽然再生障碍性贫血和癌症是不同的疾病，但许多导致再生障碍性关节炎关节和结缔组织紊乱的潜在过程也会影响癌症的进展和转移。从系统角度看，再生障碍性贫血可导致细胞浸润和肺部炎症。几项研究已经报道了再生障碍性贫血和乳腺癌之间具有统计学意义的风险比。尽管有这些知识可用，但与乳腺癌相关的乳腺癌、关节炎和转移的研究很少。值得注意的是，这两种疾病在绝经后的老年女性中都非常常见。方法：为了建立关节炎引起的炎症和乳腺癌相关的继发转移之间的新联系，在9周龄和18周龄的PYV MT小鼠自发发展为乳腺癌的情况下，注射II型胶原(CII)以诱导关节炎的转移前和转移状态。结果：随着原发肿瘤负担的增加，与非关节炎PYV MT小鼠相比，关节炎小鼠乳腺癌相关的继发肺和骨骼转移显著增加。我们报道了在关节炎的肺、骨环境和循环中，间质细胞和促炎细胞因子如白介素17(IL-17)、白介素6(IL-6)、前基质金属肽酶9(Pro-MMP9)、胰岛素样生长因子-II(GF-II)和巨噬细胞集落刺激因子(M-CSF)的水平显著增加。这些促炎细胞因子和炎性微环境可能是促进关节炎PYV MT小鼠肿瘤进展和转移的潜在因素。塞来昔布的治疗进一步证实了这一点，塞来昔布是一种抗炎药物+αIL-17抗体，显著减少了对肺和骨的继发转移。结论：所产生的数据不仅揭示了关节炎患者骨和肺转移的潜在机制，而且我们的联合治疗可能导致能够减轻肿瘤负担的治疗方式，并防止乳腺癌关节炎患者的复发和转移。
Background: Several 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.Methods: To 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.Results: A 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 + alpha IL-17 antibody that significantly reduced the secondary metastasis to lung and bone.Conclusions: The 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.