Figure 1.
Crosstalk between CRC cells and different components of the TME. Schematic representation of the reciprocal communication network of colorectal cancer cells with the cell types that compose the tumor niche. Cells communicate mainly through soluble factors such as cytokines and chemokines, metabolites and extracellular vesicles, influencing tumor growth, immune responses, angiogenesis, and therapeutic outocomes in colorectal cancer. In each box are indicated the main soluble factors secreted by each cell type, that trigger pro‐tumoral pathways. Black arrows indicate direct communication, while dashed arrows signify indirect communication, not mediated by secreted factors. Among the principal components of the TME, cancer‐associated fibroblasts (CAFs) play a role in supporting colorectal cancer growth. CAFs and cancer cells exert a mutual influence by the indicated soluble cues (from CAFs to cancer cells,[ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ] from cancer cells to CAFs.[ 21 , 24 , 36 , 40 , 41 , 42 , 43 ] Tumors require a blood supply for nutrients and oxygen. Blood vessels within the TME, known as tumor vasculature, can be abnormal, leaky, and disorganized. Cancer cells stimulate endothelial cells’ proliferation and neovascularization by releasing VEGF in the TME.[ 44 ] The presence of cancer cells can trigger visceral adipose tissue to adopt an inflammatory pro‐tumoral phenotype,[ 46 ] which in turn, produces molecules and metabolites that sustain tumor outgrowth.[ 45 , 46 , 47 , 48 , 49 , 50 , 51 ] The immune system, namely T cells, B cells, natural killer (NK) cells, macrophages, and dendritic cells, infiltrate the TME. They interact with cancer cells and can have both pro‐tumor and anti‐tumor effects. Here we reported secreted factors produced by immune cells that sustain pro‐tumoral adaptation of cancer cells,[ 52 , 53 , 54 , 55 , 56 ] and those secreted by cancer cells that induce a pro‐tumoral phenotype in immune cells.[ 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ] The enteric nervous system has a pivotal role in physiological intestine functions. When properly stimulated by cancer cells,[ 63 , 66 ] it can sustain colorectal cancer stem cells self‐renewal and tumorigenesis, proliferation and metastatic spread.[ 63 , 64 , 65 , 66 , 67 , 68 , 69 ] The intestinal microbiota can strongly impact tumor behaviour, by releasing in the TME metabolites and signaling molecules,[ 70 , 71 ] causing local inflammation or genetic damage of colonic epithelial cells and subsequent oncogenic transformation. Cells resident in metastatic sites communicate with cancer cells and support their homing and growth by secreting specific factors within the niche. Here, we represented hepatocytes and their secreted factors as the more abundant cell type in the liver, the most frequent metastatic site for CRC.[ 72 , 73 ]