New Insights on How an Inflammatory Tumor Microenvironment Promotes Invasion and Early Stage Breast Cancer Metastasis

The propensity of primary breast cancer to invade and metastasize has been partially explained by high levels of endogenous inflammation. However, it is not fully understood how inflammatory mediators, expressed either by the primary breast cancer cells or cells of the tumor microenvironment (TME), specifically contribute to metastasis. Our lab has been studying how oncostatin M (OSM), an interleukin-6 (IL-6)-family inflammatory cytokine, promotes the development of early metastatic properties distinct from IL-6 and other family members. Human breast tissue microarray analysis shows that OSM is expressed at highest levels in the precancerous epithelial cells of ductal carcinoma in situ (DCIS), suggesting a role for autocrine-produced OSM in invasive potential. Tumor-associated neutrophils (TANs) release large amounts of OSM when they come into contact with breast cancer cells, and this paracrine-produced OSM induces invasive capacity. Employing human breast and mouse mammary orthotopic xenograft and syngeneic mouse models, OSM promotes metastasis to bone, lung, and other organs. Furthermore, OSM increases circulating tumor cell (CTC) numbers that are reduced in an OSM knockout background, demonstrating the importance of paracrine-produced OSM in this process. When supported by in vitro results, where OSM induces breast tumor cell epithelial-mesenchymal transition (EMT), protease secretion, and detachment, our findings suggest a role for OSM in early stage metastasis. Finally, the importance of OSM relative to IL-6 in these processes will be discussed, and as anti-IL-6 cancer therapies (i.e. siltuximab) are failing in clinical trials, our results suggest that OSM may be the more rational target. Collectively, these data suggest that OSM, whether TME- or autocrine-produced, is a critical factor driving breast cancer invasion and tumor cell dissemination with subsequent metastasis.