Oncotarget: TAK1 regulates the tumor microenvironment

Volume 11, Issue 21 of @Oncotarget reported that in this study the authors evaluated the potential therapeutic capacity of TAK1 inhibition on tumor growth and on tumor microenvironment remodeling.

In a screen of 16 cancer cell lines, takinib in combination with tumor necrosis factor was found to induce cell death in 6 out of 16 cell lines.

Histological and proteomic analysis of TAK1KO tumors showed altered angiogenic signaling and inflammatory signaling via immune cells.

Dr. Timothy A.J. Haystead from The Department of Pharmacology and Cancer Biology at Duke University School of Medicine said, "The role of immune cells and inflammation has been widely associated with aggressiveness and survival rates in many tumors, wherein pro-inflammatory signaling within the tumor microenvironment stimulates tumor cell growth and metastasis."

"The role of immune cells and inflammation has been widely associated with aggressiveness and survival rates in many tumors, wherein pro-inflammatory signaling within the tumor microenvironment stimulates tumor cell growth and metastasis"

- Dr. Timothy A.J. Haystead, The Department of Pharmacology and Cancer Biology at Duke University School of Medicine

The role of immune cells and inflammation has been widely associated with aggressiveness and survival rates in many tumors, wherein pro-inflammatory signaling within the tumor microenvironment stimulates tumor cell growth and metastasis.

TAMs can influence the tumor microenvironment through secretion of biologically active molecules that promote tumor growth, angiogenesis, and metastasis while limiting critical anti-tumor immune responses.

TAMs enhance the tumor microenvironment in large part due to hyper-activating nuclear factor kappa-light-chain-enhancer of activated B cell signaling, leading to downstream pro-inflammatory, pro-survival, and metastatic phenotypes.

The constant exposure to inflammatory signals not only enhances the survival/growth mechanisms in tumor cells but also educates T and dendritic cells to adopt an immunosuppressive phenotype and aid in disease progression.

Figure 1: The anti-cancer effects of takinib in vitro is shown across various cell lines. Cells were plated at 80-90% confluency, serum starved for 24 hours, and evaluated 24 hours post treatment for percent cell death of takinib, takinib + TNF treatments; cell lines grouped by tissue.

Immunotherapies aimed at re-educating immune cells to adopt tumor surveillance phenotypes have shown great promise in immune responsive tumors.

The Haystead Research Team concluded in their Oncotarget Research Article that additionally, often genetic instability in the cancer cells allows for mutations to occur, leaving the cells immune to the kinase inhibitor effects or induction of compensatory mechanisms.

However, therapies targeting TAK1 appear to have effects not only at the cancer cell level but additionally at modulating the immune microenvironment.

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DOI - https://doi.org/10.18632/oncotarget.27606

Full text - https://www.oncotarget.com/article/27606/text/

Correspondence to - Timothy A.J. Haystead - Timothy.Haystead@Duke.edu

Keywords - TAK1, breast cancer, therapeutic, inflammation

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