OSM potentiates preintravasation events, increases CTC counts, and promotes breast cancer metastasis to the lung

Abstract

BackgroundSystemic and chronic inflammatory conditions in patients with breast cancer have been associated with reduced patient survival and increased breast cancer aggressiveness. This paper characterizes the role of an inflammatory cytokine, oncostatin M (OSM), in the preintravasation aspects of breast cancer metastasis.MethodsOSM expression levels in human breast cancer tissue samples were assessed using tissue microarrays, and expression patterns based on clinical stage were assessed. To determine the in vivo role of OSM in breast cancer metastasis to the lung, we used three orthotopic breast cancer mouse models, including a syngeneic 4T1.2 mouse mammary cancer model, the MDA-MB-231 human breast cancer xenograft model, and an OSM-knockout (OSM-KO) mouse model. Progression of metastatic disease was tracked by magnetic resonance imaging and bioluminescence imaging. Endpoint analysis included circulating tumor cell (CTC) counts, lung metastatic burden analysis by qPCR, and ex vivo bioluminescence imaging.ResultsUsing tissue microarrays, we found that tumor cell OSM was expressed at the highest levels in ductal carcinoma in situ. This finding suggests that OSM may function during the earlier steps of breast cancer metastasis. In mice bearing MDA-MB-231-Luc2 xenograft tumors, peritumoral injection of recombinant human OSM not only increased metastases to the lung and decreased survival but also increased CTC numbers. To our knowledge, this is the first time that a gp130 family inflammatory cytokine has been shown to directly affect CTC numbers. Using a 4T1.2 syngeneic mouse model of breast cancer, we found that mice bearing 4T1.2-shOSM tumors with knocked down tumor expression of OSM had reduced CTCs, decreased lung metastatic burden, and increased survival compared with mice bearing control tumors. CTC numbers were further reduced in OSM-KO mice bearing the same tumors, demonstrating the importance of both paracrine- and autocrine-produced OSM in this process. In vitro studies further supported the hypothesis that OSM promotes preintravasation aspects of cancer metastasis, because OSM induced both 4T1.2 tumor cell detachment and migration.ConclusionsCollectively, our findings suggest that OSM plays a crucial role in the early steps of metastatic breast cancer progression, resulting in increased CTCs and lung metastases as well as reduced survival. Therefore, early therapeutic inhibition of OSM in patients with breast cancer may prevent breast cancer metastasis.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0971-5) contains supplementary material, which is available to authorized users.

Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells

“…Of note, MIP‐1α and PDGF‐BB are also negative regulators of osteoblast differentiation . Another cytokine expressed by MDA‐EVs was oncostatin M (OSM), which potentiates preintravasation of breast cancer cells and their ability to metastasize the lung and the bone …”

Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery

“…Recently, the cytokine oncostatin M was found to induce EMT, tumor cell detachment and migration as well as increasing the expression of VEGF and MMP, both accelerating intravasation of tumor cells . Interestingly, in a lung cancer model, oncostatin knock‐out mice had reduced CTC, fewer lung metastases and increased overall survival .…”

“…Recently, the cytokine oncostatin M was found to induce EMT, tumor cell detachment and migration as well as increasing the expression of VEGF and MMP, both accelerating intravasation of tumor cells . Interestingly, in a lung cancer model, oncostatin knock‐out mice had reduced CTC, fewer lung metastases and increased overall survival . Furthermore, proteoglycans have been shown to be extensively involved in the migration of tumor cells as demonstrated by Chondroitin Sulfate A that mediates focal adhesion and motility, while blocking Chondroitin Sulfate A inhibited cellular migration and metastasis formation …”

GP130 Cytokines in Breast Cancer and Bone

“…In the context of breast cancer bone metastasis, one group has shown that OSM knockdown in 4T1 mouse mammary carcinoma cells reduced spontaneous metastasis to the spine, as assessed by qPCR analysis following orthotopic injections, and less osteolytic bone destruction following intratibial injections [125]. This group also demonstrated that the global knockdown of OSM in Balb/c mice reduced the formation of spontaneous lung metastases [126]. These data suggest that autocrine OSM promotes bone metastasis, and paracrine OSM signaling promotes lung metastasis, but the mechanism by which OSM acts in vivo to stimulate metastasis remains unclear.…”