Pro-inflammatory TNF-α and IFN-γ Promote Tumor Growth and Metastasis via Induction of MACC1

Abstract

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Early stage CRC patients have a good prognosis. If distant metastasis occurs, the 5-year survival drops below 10%. Despite treatment success over the last decades, treatment options for metastatic disease are still limited. Therefore, novel targets are needed to foster therapy of advanced stage CRC patients and hinder progression of early stage patients into metastasis. A novel target is the crucial oncogene Metastasis-Associated in Colon Cancer 1 (MACC1) involved in molecular pathogenesis of CRC metastasis. MACC1 induces cell proliferation and motility, supports cellular survival and rewires metabolism resulting in increased metastasis in vivo. MACC1 is a prognostic biomarker not only for CRC but for more than 20 solid cancer entities. Inflammation plays a pivotal role in tumorigenesis, tumor progression and metastasis. For CRC, inflammatory bowel disease and ulcerative colitis are important inflammation associated risk factors. Certain cytokines, such as TNF-α and IFN-γ, are key factors in determining the contribution of the inflammatory process to CRC. Knowledge of the connection between inflammation and MACC1 driven tumors remains unclear. Gene expression analysis of CRC cells after cytokine stimulation was analyzed by qRT-PCR and Western blot. Cellular motility was assessed by Boyden chamber assays. MACC1 promoter activity after stimulation with pro-inflammatory cytokines was measured using promoter-luciferase constructs. To investigate signal transduction from receptor to effector molecules, blocking experiments using neutralizing antibodies and knockdown experiments were performed. Following TNF-α stimulation, MACC1 and c-Jun expression were significantly increased at the mRNA and protein level. Knockdown of c-Jun reduced MACC1 inducibility following TNF-α stimulation. TNF-α promoted MACC1-induced cell migration that was reverted following MACC1 knockdown. Moreover, MACC1 and c-Jun expression were downregulated by blocking TNFR1, but not TNFR2. Knock down of the NF-κB subunit, p65, reduced basal MACC1 and c-Jun mRNA expression levels. Adalimumab, a clinically approved monoclonal anti-TNF-α antibody, hindered MACC1 induction. The present Kobelt et al. Inflammation-Induced MACC1 Expression study highlights that TNF-α regulates the induction of MACC1 via the NF-κB subunit p65 and the transcription factor c-Jun in CRC cells. This finding unravels a novel signaling pathway upstream of MACC1 and provides a potential therapeutic target for the treatment of CRC patients with an associated inflammation.

Phytochemical, Cytotoxicity, Antioxidant and Anti-Inflammatory Effects of Psilocybe Natalensis Magic Mushroom

“…Only the ethanol extract at the highest concentration used significantly increased the anti-inflammatory cytokine IL10 above the control in line with LNAME, while the other extracts down-regulated it in a dose-dependent manner. It is known that high levels of pro-inflammation cytokines like IL1β and TNF-α are present in the pathogenesis of many chronic diseases associated with chronic inflammation, and that they contribute to cell injury and damage and also initiate or sustain the inflammation state [ 4 , 30 ]. By suppressing the LPS-induced production of IL1β and TNF-α cytokines, the P. natalensis mushroom extracts demonstrate another positive potential benefit in chronic inflammation treatment.…”

Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut

“…Colorectal cancer is sometimes the consequence of prolonged and recurrent inflammation in the gut (colitis-associated colorectal cancer or CAC), especially in UC patients [ 144 ]. The cytokine profile in these patients acts as a decisive factor in the tumor progression and metastases [ 145 ]. A few cytokines, like TNF and IL-6, have been shown to be the driving factors that bridge these two diseases (reviewed in [ 146 ]).…”

“…The deleterious effect of TNF is confirmed by using both animal models of CRC (Apc Min/+ and AOM/DSS), where abrogation of TNF signaling strongly diminished tumor growth [ 150 ]. Additionally, TNF has also been shown to promote tumor growth and metastasis via induction of epithelial-derived oncogene MACC1 [ 145 ]. Certain cytokines, like IL-33, a member of the IL-1 family, can regulate CRC progression by controlling the tumor microenvironment (TME).…”

Harnessing Tumor Necrosis Factor Alpha to Achieve Effective Cancer Immunotherapy

“…Its role in clinical oncology is not certain, but there is evidence that proves its efficacy in inhibiting TNFα tumor-promoting properties. In colorectal cancer cells, treatment with adalimumab hindered the induction of the Metastasis-Associated in Colon Cancer 1 (MACC1), a crucial oncogene that promotes cell proliferation, motility, and survival, increasing metastasis in preclinical models [ 197 ]. The authors proved that the expression of MACC1 in inflamed tissues from ulcerative colitis and Crohn’s disease patients is upregulated by TNFα through NF-κB signaling pathway, via TNFR1, which lead to an increase in cell migration.…”