HiJAK’d Signaling; the STAT3 Paradox in Senescence and Cancer Progression

Abstract

Clinical and epidemiological data have associated chronic inflammation with cancer progression. Most tumors show evidence of infiltrating immune and inflammatory cells, and chronic inflammatory disorders are known to increase the overall risk of cancer development. While immune cells are often observed in early hyperplastic lesions in vivo, there remains debate over whether these immune cells and the cytokines they produce in the developing hyperplastic microenvironment act to inhibit or facilitate tumor development. The interleukin-6 (IL-6) family of cytokines, which includes IL-6 and oncostatin M (OSM), among others (LIF, CT-1, CNTF, and CLC), are secreted by immune cells, stromal cells, and epithelial cells, and regulate diverse biological processes. Each of the IL-6 family cytokines signals through a distinct receptor complex, yet each receptor complex uses a shared gp130 subunit, which is critical for signal transduction following cytokine binding. Activation of gp130 results in the activation of Signal Transducer and Activator of Transcription 3 (STAT3), and the Mitogen-Activated Protein Kinase (MAPK) and Phosphatidylinositol 3-Kinase (PI3K) signaling cascades. Tumor suppressive signaling can often be observed in normal cells following prolonged STAT3 activation. However, there is mounting evidence that the IL-6 family cytokines can contribute to later stages of tumor progression in many ways. Here we will review how the microenvironmental IL-6 family cytokine OSM influences each stage of the transformation process. We discuss the intrinsic adaptations a developing cancer cell must make in order to tolerate and circumvent OSM-mediated growth suppression, as well as the OSM effectors that are hijacked during tumor expansion and metastasis. We propose that combining current therapies with new ones that suppress the signals generated from the tumor microenvironment will significantly impact an oncologist’s ability to treat cancer.

Effect of human papillomavirus 16 oncoproteins on oncostatin M upregulation in oral squamous cell carcinoma

“…Normally, it inhibits growth and promotes cellular senescence. However, dysregulated OSM expression can promote cell survival, proliferation and metastasis [9]. Dysregulated c-Myc, commonly found in various cancers, can inhibit the senescence induced by OSM, and subsequently, OSM function switches to oncogenic mechanisms [14,15].…”

“…The main source of OSM is immune cells. Keratinocytes, as well as cancer cells, can also produce high OSM levels [7,9]. In keratinocytes, keratinocyte growth factor (KGF) can stimulate OSM expression via KGF receptor (KGFR) signaling in human keratinocytes (skin), resulting in the induction of neighboring keratinocytes and fibroblasts via autocrine and paracrine pathways, respectively, leading to cell migration and angiogenesis through the OSM-activated STAT3-targeted urokinase mediated plasminogen activation (uPA) system [7].…”

“…It has been reported previously that OSM can promote IL-6, STAT3 induction and increase c-Myc expression [9,12,13]. We therefore examined levels of each of these in HCK1T cells overexpressing HPV16E6 (Dox ?…”

“…OSM acts as an autocrine and a paracrine agent that can bind to the LIF/gp130 and OSMR/gp130 receptors on the surface of target cells, stimulating many signaling cascades and subsequently promoting cell survival, proliferation, migration and metastasis [9]. We determined the levels of the secreted form of OSM in mock and E6/E7-transfected ORL-48(T) and ORL-136(T) culture medium.…”

“…OSM stimulates the target cells in both autocrine and paracrine modes via binding to appropriate receptors (OSMR/gp130 and LIFR/ gp130) and subsequently induces many signaling cascades to promote several biological consequences such as growth inhibition, inflammatory response and cell differentiation. Interestingly, dysregulated OSM promotes cell survival, cell proliferation and tumorigenesis [9].…”