The Colorectal Tumor Microenvironment: The Next Decade

Abstract

Colorectal cancer cells establish a crosstalk with the tumor microenvironment, such that implantation and development of the tumor is generally favoured. CRC progression depends on mutations in the tumor's oncogenic pathways as well as metastasis suppressor genes, but is also influenced by the inflammatory components in the microenvironment. Inflammation results from the dietary intakes and is either compounded or counterbalanced by our lifestyles. Whether driven by intrinsic pathways or infection, inflammation produces a massive influx of cytokines and chemokines. Currently, in colorectal cancer, the best approach to counter this inflammatory wave in the microenvironment appears to be CCL2 cytokine targeting. A fairly new avenue of discovery has identified microRNAs regulating colorectal cancer-mediated inflammation, and in particular the IL-6 pro-inflammatory pathway that induces pro-apoptotic genes and HIF1α-elicited VEGF secretion. miRNAs also play a significant role in controlling metabolic genes such as the upregulation of the fatty acid synthase gene with the concomitant down-regulation of the carnitine palmitoyl transferase 1 gene. Within the metastatic environment, the Discoidin domain receptor-2 (DDR2) gene encodes a tyrosine kinase receptor for fibrillar collagen that contributes to colorectal cancer metastasis by increasing myofibroblasts, neoangiogenic vessels and proliferating cancer cells. Ongoing identification of gene signatures differentiating between primary tumor cells and their metastatic counterparts promises a wealth of new targets to be exploited for further therapeutic use within the next decade.Keywords Colorectal cancer . Microenvironment . Inflammation . Cytokines . Chemokines . CCL2 . miRNA . DDR2 Although significant avenues have been exploited in the recent few years to extend the life and enhance the quality of the life of patients treated for colorectal cancer (CRC), the challenges of preventing and treating CRC and its metastases remain very demanding. Yet, the enormous research efforts of the last decade promise major discoveries and novel implementation relative to potential treatments for CRC that will hopefully be available within the next 10 years. New findings implicating mutations in metastasis suppressor genes [1] or in known oncogenic pathways such as KRAS, BRAF, PTEN, IGFR1 and EGFR [2-4] as well as epigenetic alterations involving DNA methylation dysregulation and/or chromatin remodeling [5] and miRNA control of gene expression [6] have greatly expanded the knowledge of how metastatic dissemination proceeds. The constant interplay between the tumor and its surrounding microenvironment continuously modifies their synergistic mechanisms and responses generally to the tumor's advantage, such that attacking the lesions on all fronts becomes a necessity. Thus, monitoring and dampening the microenvironment inflammation whether by dietary changes or by appropriately targeted specific or systemic interventions as well as blocking receptormediated triggering by angiog...

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“…6,7 There is some evidence that cancer cells establish a profitable interplay with bystander cells of their microenvironment, to receive help for growth and metastasis, nutrition and protection from immune recognition. 8 The cross talk between tumor and stroma occurs through the modulation/release of nucleic acid messengers (DNA, mRNA and microRNAs [miRNAs]) and soluble factors acting locally and at a distance to modify the cells' behavior. These modulators are ultimately detectable in peripheral blood, where they can serve as biological markers of cell transformation useful for early diagnosis and for predictive and prognostic purposes for developing minimally invasive lowburden screening tests.…”