Over the past decade, growing evidence indicates that the tumor microenvironment (TME) contributes with genomic/epigenomic aberrations of malignant cells to enhance cancer cells survival, invasion, and dissemination. Many factors, produced or de novo synthesized by immune, stromal, or malignant cells, acting in a paracrine and autocrine fashion, remodel TME and the adaptive immune response culminating in metastasis. Taking into account the recent accomplishments in the field of immune oncology and using metastatic colorectal cancer (mCRC) as a model, we propose that the evasion of the immune surveillance and metastatic spread can be achieved through a number of mechanisms that include (a) intrinsic plasticity and adaptability of immune and malignant cells to paracrine and autocrine stimuli or genotoxic stresses; (b) alteration of positional schemes of myeloid-lineage cells, produced by factors controlling the balance between tumour-suppressing and tumour-promoting activities; (c) acquisition by cancer cells of aberrant immune-phenotypic traits (NT5E/CD73, CD68, and CD163) that enhance the interactions among TME components through the production of immune-suppressive mediators. These properties may represent the driving force of metastatic progression and thus clinically exploitable for cancer prevention and therapy. In this review we summarize results and suggest new hypotheses that favour the growing impact of tumor-infiltrating immune cells on tumour progression, metastasis, and therapy resistance. 1. Introduction More than 1.2 million colorectal cancers (CRCs) are diagnosed every year worldwide, accounting for approximately 10% of all cancers [1, 2]. The death rate from CRC has been dropping for more than 20 years, mostly due to earlier screenings and improved treatments. In spite of this, CRC remains the fourth most common cause of cancer-related death in western countries [1–5]. Recent evidence suggests that accumulation of genetic and epigenetic alterations in malignant colonic cells progresses through at least three distinct pathways: chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP) [6–8]. CIN is the most common type of genomic instability occurring in 60%–80% of CRCs and results in an imbalance of the chromosome number “manifested as aneuploidy.” MSI is an alternative pathway, accounting for 15–20% of sporadic CRCs in which the characteristic signature is deletion of repetitive regions of DNA that in most cases generates frameshift mutations in the coding sequences of genes leading to
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