## 3 Indirect Communication in the Tumor Microenvironment
### Soluble Mediators
It can not only inhibit the anti-tumor action of lymphocytes but also promote the tumor phenotype, which is more difficult for the immune system to recognize [72]. Its elevated levels in tumors and serum of CRC patients correlate with poor prognosis, explained by the increased migratory and invasive capabilities of tumor cells. This effect may be associated with an upregulation of the calcium-associated tumor transducer 2 (TROP-2) signaling protein. Studies on colorectal cancer cells have shown an elevated level of TROP-2, dependent on the TNF-\(\alpha\) concentration [73]. Another study showed a significant increase in TNF-\(\alpha\) mRNA and TNF-\(\alpha\) levels in the serum of patients with advanced colorectal cancer compared to earlier stages. All these data point to the role of TNF-\(\alpha\) in promoting colorectal cancer invasion [74; 75]. In general, IL-1\(\beta\), IL-6, and TNF-\(\alpha\) can be useful significant diagnostic markers in CRC and potential therapeutic targets. However, their application in CRC therapy requires further research. So far, several drugs targeting these proinflammatorycytokines have been approved (e.g., canakinumab, etanercept, and tocilizumab), but mainly in therapies for inflammatory diseases rather than cancer [62; 76; 77; 78]. IL-8 (CXCL-8) is a pro-inflammatory cytokine that has an affinity for the C-X-C motif chemokine receptor (CXCR). It is produced by the epithelium and most immune cells, but it also acts as a chemoattractant for many of these cells (including acute inflammatory neutrophils) as well as endothelial cells, thus mediating the angiogenesis process. Its level increases in response to specific conditions, such as hypoxia or the presence of other pro-inflammatory cytokines (including TNF-\(\alpha\) and IL-1) [60; 79; 80]. In CRC, elevated levels of IL-8 are associated with cancer invasion [81]. IL-8 is involved in the progression of colorectal cancer, mainly through the development of liver metastases and resistance to chemotherapy. By binding to membrane receptors on the surface of cancer stem cells (CSCs), IL-8 mediates the migration and invasion of CSCs and the production of EMT inducers [82]. The use of specific IL-8 antagonists is a promising strategy for cancer treatment, as increased sensitivity of CRC cells to cytostatic agents has been observed after introducing the CXCR-2 antagonist SCH-527123 into treatment [83]. The pro-inflammatory cytokines of the CRC microenvironment also include the IL-17, IL-1, and IL-12 families. Anti-inflammatory cytokines include IL-4, IL-10, and IL-13. Moreover, a number of pleiotropic cytokines have both pro- and anti-inflammatory effects (e.g., interferon \(\gamma\) IFN-\(\gamma\)) [60]. In the CRC microenvironment, most cytokines are associated with tumor-promoting effects [52]. Indirect mediators also include chemokines, which constitute the most numerous subgroup of cytokines. Similar to other cytokines, they exhibit a wide range of actions specific to different types of cancer [52]. Initially, they were correlated only with the ability to target immune cells, but recent discoveries suggest that chemokines are also involved in controlling reprogrammed cells to maintain tumor progression. In CRC, the C-C motif chemokine ligand 2 (CCL-2) is the pro-tumor chemokine, and its presence correlates with poor prognosis. This effect is the result of action mainly on niche cells that maintain a suppressive environment for normal immune cells. It has been shown that the chemokine CCL-2 may be associated with the infiltration of unfavorable M2 macrophages. In turn, chemokines from the group of C-X-C motif chemokines (CXC) are strong chemoattractrs for neutrophils [52; 84].