The Role Of Tumor Immune Microenvironment And Metabolism In Progression And Metastasis Of Hepatocellular Carcinoma

Liver cancer is a heavy burden for human health. Recurrence and metastasis were key factors influencing overall survival of liver cancer patients. Due to the intrahepatic satellite tumor and multi-central tumor, the postoperative 5-year recurrence rate of hepatocellular carcinoma (HCC) reaches 61.5%. In order to gain insight into tumor, not only we should focus on the tumor cell itself, the tumor milieu should not be ignored. Tumor microenvironment plays an important role in tumor initiation and progression. The tumor cells and stromal cells in tumor microenvironment are in mutually evolution. Stromal cells influence the entire procedure of tumor cells, ranging from tumor initiation to metastasis. They performed as enhancer or inhibitor of tumor. In turn, tumor cells modulate stromal physico-chemical property, intergradient, and cytokine which lead to tumor environment facilitating tumor growth.Cancer cells can reprogram their glucose metabolism, and thus their energy production, by limiting their energy metabolism largely to glycolysis, leading to a state that has been termed "aerobic glycolysis".Glycolytic fueling has been shown to be associated with activated oncogenes (e.g., RAS, MYC) and mutant tumor suppressors, whose alterations in tumor cells have been selected primarily for their benefits in conferring the hallmark capabilities of cell proliferation, avoidance of cytostatic controls, and attenuation of apoptosis. Thus, realizing the molecular mechanisms of tumor microenvironment and cancer metabolism in promoting HCC invasion and metastasis is of great importance.The recruitment of myofibroblats originates from normal fibroblasts contributes to malignant behaviors of tumor including tumor proliferation, angiogenesis, invasion, and metastasis. The cross-talk between cancer-associated fibroblasts (CAF) and tumor cells is accentuated in multiple tumors. A wealth of cytokines is secreted by CAF to facilitate tumor invasion and metastasis. Meanwhile, tumor cells secrets TGF-β and PDGF to contribute quiescent hepatic stellate cells differentiate into CAF. Recent research found that tumor cells secrets H2O2 to induce CAF underwent autophagy, mitochondrial autophagy, and aerobic glycolysis. This parasite-like metabolic inertsections make stroma performed as "energy factory" for tumor cells. CAF secrets multiple recycled metabolic product (lactate, glutaminate) to contribute to mitochondrial oxidative metabolism. We found that after cell co-culture, LX-2 underwent metabolic reprogramming, and migration and invasion of HCC cells were enhanced. TIM-1 may play an important role between the immunologic cross-talk of HCC cells and LX-2.TIM-1 is expressed in Th2 cells and plays an important role in asthma and ischemia-reperfusion injury [9]. TIM-1 was highly expressed in colorectal cancer and is inversely correlated with prognosis, overexpression decreased affinity of tumor cells. TIM-1 contributed to malignant behaviors of clear cell renal cell carcinoma via IL-6/STAT3 pathway and was associated with worse prognosis. We found that TIM-1 expression was increased in highly metastatic HCC cells lines and tumor tissues. TIM-1 may contribute to HCC progression by inducing CCL2, CCL5 and CCL21 secretion. Moreover, TIM-1 may promote HCC migration and invasion by recuiting adaptive cells infiltration. TIM-1 was associated with migration, invasion, and poor prognosis of HCC.PKM2 is a key enzyme in tumor Warburg effect, PKM2 is overexpressed in multiple tumors. PKM2 overexpressed tumor cells proliferated higher than PKM1 overexpressed tumor cells [12]. PKM2 bound to HIF-1α and transcriptionally activated SLC2A1, LDH, and PDK1 [13]. PKM2 may contribute to HCC progression via PI3K-Akt and JNK pathway, moreover, PKM2 may promotes HCC migration and invasion by recuiting MDSC infiltration. Finally, PKM2 may serve as a novel prognostic indicator for HCC patients after curative resection.MDSCs are a group of heterogeneous immature myeloid-derived cells; they proliferated under pathological conditions and inhibited immune responses. MDSCs accumulated by the inductions of cytokine, inhibit anti-tumor immunity by multiple mechanisms and contribute tumor angiogenesis and metastasis. We found that the proportion of MDSCs in peripheral blood and tumor site of HCC patients was higher than healthy control.The comprehensive relationships within immune microenvironment, metabolism, and tumor progression and metastasis are gaining increasing attention. Tumor microenvironment contributed to the inactivated/dysfunctional phenotype of tumor-associated DC (TADC) by metabolic regulation. Ppp2r2d knockdown inhibited tumoral T-cell apoptosis and enhanced T-cell proliferation as well as cytokine production. We found that TIM-1 secreted by tumor cells contributed to tumor cells proliferation and invasion, meanwhile TIM-1 may contribute to cytokine secretion to recruitment of adaptive immunogical cells infiltration to achieve immune escape. PKM2 which is a key enzyme in tumor metabolism contributed to malignant phenotype of tumor cells and could modulate immune microenvironment. Our study found that PKM2 could recruit MDSC and TAM infiltration. Our study lay theoretical foundation for tumor comprehensive therapy.Conclusion1. The migration and tube formation ability of HCC cells were enhanced by conditioned medium after cell co-culture.2. LX-2 underwent metabolic reprogramming, and migration and invasion of HCC cells were enhanced after LX-2 and HCC cells co-culture.3. TIM-1 contributes to malignant behaviors of HCC in vitro and in vivo.4. TIM-1 may contribute to HCC progression by inducing CCL2, CCL5 and CCL21 secretion to recuiting adaptive immunologic cells infiltration.5. TIM-1 was associated with migration, invasion, and poor prognosis of HCC.6. Data obtained from cell lines, tumorigenicity studies, and primary HCC samples illustrate an oncogenic role for PKM2 in tumors.7. PKM2 may promote HCC migration and invasion by recuiting MDSC infiltration.8. PKM2 may serve as a novel prognostic indicator for HCC patients after curative resection.9. The proportion of MDSCs in peripheral blood and tumor site of HCC patients was higher than healthy control. MDSCs were isolated in ascites of advanced HCC patients.Research Prospect1. Our research initially illustrates the role of tumoral inflammatory microenvironment in HCC invasion and metastasis. More in-depth investigations are warranted to realize the mechanisms.2. Clarify whether CAF contributes to HCC malignancy by autophagy.3. Investigate the impact of TIM-1 on adaptive immune cells and the interactions between TIM-1 and CCL2, CCL5, and CCL21.4. Realize the influence of TIM-1 on HCC autophagy.5. Verify the direct relationships between PKM2 and CCL8, CCL2, CXCL1, and MIF.6. Gain insight into the intracellular regulated genes in MDSC to realize the in-depth function of MDSC in HCC.