Monocytes/macrophages support mammary tumor invasivity by co-secreting lineage-specific EGFR ligands and a STAT3 activator

Abstract

BackgroundTumor-associated macrophages (TAM) promote malignant progression, yet the repertoire of oncogenic factors secreted by TAM has not been clearly defined. We sought to analyze which EGFR- and STAT3-activating factors are secreted by monocytes/macrophages exposed to tumor cell-secreted factors.MethodsFollowing exposure of primary human monocytes and macrophages to supernatants of a variety of tumor cell lines, we have analyzed transcript and secreted protein levels of EGFR family ligands and of STAT3 activators. To validate our findings, we have analyzed TAM infiltration levels, systemic and local protein levels as well as clinical data of primary breast cancer patients.ResultsPrimary human monocytes and macrophages respond to tumor cell-derived factors by secreting EGFR- and STAT3-activating ligands, thus inducing two important oncogenic pathways in carcinoma cells. Tumor cell-secreted factors trigger two stereotype secretory profiles in peripheral blood monocytes and differentiated macrophages: monocytes secrete epiregulin (EREG) and oncostatin-M (OSM), while macrophages secrete heparin-binding EGF-like growth factor (HB-EGF) and OSM. HB-EGF and OSM cooperatively induce tumor cell chemotaxis. HB-EGF and OSM are co-expressed by TAM in breast carcinoma patients, and plasma levels of both ligands correlate strongly. Elevated HB-EGF levels accompany TAM infiltration, tumor growth and dissemination in patients with invasive disease.ConclusionsOur work identifies systemic markers for TAM involvement in cancer progression, with the potential to be developed into molecular targets in cancer therapy.

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

“…71 Coupled with these findings is the observation that OSM is secreted by macrophages localized at the advancing, infiltrative margins of carcinomas, where invasive tumor cells reside and intravasate during metastasis. 22 The unique signaling that emanates from OSMRb/gp130 receptor complexes discussed above may explain why elevated OSM in the TME correlates with more invasive, metastatic tumors, as CD44-expressing cancer cells, recently classified as metastasis-initiating cells, are also found primarily at the invasive edge of tumors. 22,71 In addition, DNA damaging chemotherapy induces additional OSM secretion from macrophages, potentially increasing mesenchymal and CSC properties following treatment with genotoxic therapies.…”

“…22 The unique signaling that emanates from OSMRb/gp130 receptor complexes discussed above may explain why elevated OSM in the TME correlates with more invasive, metastatic tumors, as CD44-expressing cancer cells, recently classified as metastasis-initiating cells, are also found primarily at the invasive edge of tumors. 22,71 In addition, DNA damaging chemotherapy induces additional OSM secretion from macrophages, potentially increasing mesenchymal and CSC properties following treatment with genotoxic therapies. 90,95,96 When found together in tumors, dysregulated MYC and increased OSM create the potential for invasive, metastatic, and potentially therapyresistant cancer cells.…”

“…There is mounting evidence that OSM in the TME contributes to tumor progression. 1,[19][20][21][22][23][24]28,33,74,[87][88][89][90][91][92][93] For example, in addition to the increased OSM levels in the breast TME, breast cancer cells also display elevated OSMR expression levels, which is associated with adverse clinical outcomes. 32,71,83,88,92,94 Notably, the more aggressive basal-like or triple-negative breast cancer subtype expresses markedly higher levels of OSMR when compare with the less aggressive luminal subtype.…”

“…[13][14][15][16][17][18] Elevated levels of OSM in the TME are associated with highly aggressive metastatic cancers, increased risk of tumor recurrence, and a poor prognosis. [19][20][21][22][23][24] In breast cancer, OSM is concentrated at the invasive edges of highly metastatic tumors where cells often display mesenchymal cell characteristics and express the cancer stem cell marker CD44. 22,25 Whereas OSM drives proliferation, epithelial-mesenchymal transition (EMT), invasion, and metastasis in breast cancer cells and transformed human mammary epithelial cells (HMEC), it engages senescence in normal and non-transformed HMEC.…”

“…[19][20][21][22][23][24] In breast cancer, OSM is concentrated at the invasive edges of highly metastatic tumors where cells often display mesenchymal cell characteristics and express the cancer stem cell marker CD44. 22,25 Whereas OSM drives proliferation, epithelial-mesenchymal transition (EMT), invasion, and metastasis in breast cancer cells and transformed human mammary epithelial cells (HMEC), it engages senescence in normal and non-transformed HMEC. 13,[19][20][21][26][27][28][29][30][31][32][33][34] Senescence is an irreversible, proliferationinhibiting response that occurs in 2 steps: 1) reversible cell cycle arrest followed by 2) futile growth-induced gerogenic conversion, or geroconversion.…”