The role of pro-inflammatory cytokines and immune cells in colorectal carcinoma progression

Abstract

Cytokines exhibit a pleiotropic effect in the regulation of the immune cell function, tumor growth and antitumor immune responses. A total of 30 patients with colorectal carcinoma were enrolled on this study and their levels of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, serum granulocyte colony-stimulating factor (sG-CSF) and serum macrophage colony-stimulating factor (sM-CSF) were measured preoperatively using ELISA. Tumor-infiltrating granulocyte (TIG), tumor-associated macrophage (TAM), G-CSF and M-CSF expression in tumor cells were examined using immunostaining. This study revealed abnormal levels of cytokines in patients, including IL-1β (1/30, 3.3%), IL-6 (16/30 53.3%), IL-81 (15/30, 50%), TNF-α (4/21, 19%), sG-CSF (17/30, 56.7%) and sM-CSF (4/21, 19%). There was a positive linear correlation between IL-6 and sM-CSF (P=0.017, R=0.517). sG-CSF was significantly associated with a deeper tumor invasion (P=0.039) and a more advanced tumor stage (P=0.023). The granulocyte/lymphocyte (G/L) ratio was associated with abnormal levels of sG-CSF. Logistic univariate analysis revealed that TIGs were a risk factor for lymph node metastasis (0.019) and TAMs were a risk factor for depth of invasion (0.029), but this was not confirmed in logistic multivariate analysis. In conclusion, IL-6, IL-8, sM-CSF and sG-CSF may indirectly promote tumor growth, progression and metastasis by changing the leukocyte populations in the blood and the tumor microenvironment.

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…Is it possible that the elevated neutrophil counts in cancer patients are actually the consequence of a more advanced stage, and therefore predict an apparent poorer prognosis? This was acknowledged by Liu et al [178], who showed that the NLR was significantly associated with a more advanced colorectal tumor stage. Also Ietomi [382] observed that the NLR was higher in Stage IV stomach cancer patients than those having stage I-III stomach cancer.…”

“…G-CSF was associated with a deeper tumor invasion and a more advanced tumor stage [178]. The granulocyte/lymphocyte ratio was associated with abnormal levels of G-CSF (more than 50 % of the cancer patients) and TIGs were a risk factor for lymph node metastasis in colorectal carcinoma [178].…”

“…The most common neutrophil chemoattractants produced by tumors include IL-8 (CXCL8/CXCL2), MIP-1α (CCL3), huGCP-2 (CXCL6) and KC (CXCL1) [167][168][169][170][171]. G-CSF is ectopically expressed in several human tumors such as leukemia [172], bladder [173], pancreatic [174], cervical [175], ovarian [176], head and neck [177], colorectal [178] and breast carcinoma [179]. Similarly, some human cancers show elevated GM-CSF expression levels [31,180,181].…”

“…Colorectal carcinoma sections were characterized by tumor-infiltrating granulocytes (TIGs) and tumor-associated macrophages (TAMs) and abnormal levels of the cytokines IL-1β, IL-6, IL-8, TNFα, G-CSF and M-CSF [178]. G-CSF was associated with a deeper tumor invasion and a more advanced tumor stage [178].…”

Interactions between colon cancer cells and tumor-infiltrated macrophages depending on cancer cell-derived colony stimulating factor 1

“…[13][14][15] A recent study also reported CSF1 expression in more than half (56.7%) of patients with colorectal cancer. 16 The above observations suggest that CSF1 intervention would be a feasible strategy for macrophage-related immune therapy against colon cancer. However, despite of the well-acknowledged correlations between CSF1 level and number of macrophages, there are still debates about the roles of CSF1 in cancer development.…”