Tackling the tumor microenvironment: what challenge does it pose to anticancer therapies?

Abstract

Cancer is a highly aggressive and devastating disease, and impediments to a cure arise not just from cancer itself. Targeted therapies are difficult to achieve since the majority of cancers are more intricate than ever imagined. Mainstream methodologies including chemotherapy and radiotherapy as routine clinical regimens frequently fail, eventually leading to pathologies that are refractory and incurable. One major cause is the gradual to rapid repopulation of surviving cancer cells during intervals of multiple-dose administration. Novel stress-responsive molecular pathways are increasingly unmasked and show promise as emerging targets for advanced strategies that aim at both de novo and acquired resistance. We highlight recent data reporting that treatments particularly those genotoxic can induce highly conserved damage responses in non-cancerous constituents of the tumor microenvironment (TMEN). Master regulators, including but not limited to NF-kB and C/EBP-β, are implicated and their signal cascades culminate in a robust, chronic and genome-wide secretory program, forming an activated TMEN that releases a myriad of soluble factors. The damage-elicited but essentially off target and cell non-autonomous secretory phenotype of host stroma causes adverse consequences, among which is acquired resistance of cancer cells. Harnessing signals arising from the TMEN, a pathophysiological niche frequently damaged by medical interventions, has the potential to promote overall efficacy and improve clinical outcomes provided that appropriate actions are ingeniously integrated into contemporary therapies. Thereby, anticancer regimens should be well tuned to establish an innovative clinical avenue, and such advancement will allow future oncological treatments to be more specific, accurate, thorough and personalized.

Translational Horizons in the Tumor Microenvironment: Harnessing Breakthroughs and Targeting Cures

“…Intriguingly, NF‐κB was identified as a key signaling node that actively mediates WNT16B production. Cell culture experiments and tumor xenograft models proved the protective effect of fibroblast‐derived WNT16B, indicating that WNT16B secreted by stroma attenuates cancer cell apoptosis induced by genotoxicity, and compromises drug response through activation of a DNA damage secretory program (DDSP) (Fig. ).…”

miR-526a regulates apoptotic cell growth in human carcinoma cells

“…The transcription factor nuclear factor-jB (NFjB) is a major regulator of pro-inflammatory genes including cytokines and chemokines (IL-6, RANTES and IL-8) [26]. In the process of carcinogenesis, mal-developed cells activate NF-jB pathway from intrinsic imbalance or extrinsic signals in the tumor microenvironment [27,28]. In this article, we found that miR-526a expression led to decreased cell apoptosis by TNF-a-treatment.…”

Updated Landscape of the Tumor Microenvironment and Targeting Strategies in an Era of Precision Medicine

“…The study presents new opportunities for future advanced treatments that rationally integrate agents to confine the TME activities. For instance, depleting stroma-derived WNT16B, which would specifically overcome such a "new" but not "minor" TME-associated resistance mechanism [57,60]. As supporting evidence, CAFs are similarly enriched in colorectal cancer (CRC) during the post-therapy stage and display enhanced cytokine IL-17A, which helps maintain the tumor infiltrating cells (TICs) through activation of NF-κB signaling [61].…”

“…Upon genotoxic insults, NF-κB acts as a key signaling node that actively mediates WNT16B production. Cell-based experiments and tumor transplant models demonstrated the protective effect of fibroblast-derived WNT16B, indicating that WNT16B secreted by stroma attenuates cancer cell apoptosis induced by genotoxicity, and counteracts drug response through activation of a DNA damage secretory program (DDSP) [56][57][58][59] (Figure 2). The study presents new opportunities for future advanced treatments that rationally integrate agents to confine the TME activities.…”

“…To date, an array of agents are developed to minimize these activities, particularly small molecule inhibitors against key signal pathway nodes including the ATM/ATR-associated DDR repair machinery, p38MAPK cascade, mTOR subunits, JAK/STAT axis, NF-κB complex and CCAAT/enhancer binding protein (C/EBP) components. Alternatively, cytostatic antibodies with the ability to neutralize major soluble factors of significant roles in shaping advanced cancer phenotypes, such as those targeting MMPs, IL-6, IL-8, WNT16B, SFRP2, SPINK1 and AREG are also strong candidates that can be exploited to target the TME [57]. Fortunately, a handful of agents successfully acquired FDA approval for the systemic intervention of cancer patients while many others are in the industrial pipelines or clinical trials.…”