CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion.

Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) are among the most important and abundant players of the tumor microenvironment. CAFs as well as TAMs are known to play pivotal supportive roles in tumor growth and progression. The number of CAF or TAM cells is mostly correlated with poor prognosis. Both CAFs and TAMs are in a reciprocal communication with the tumor cells in the tumor milieu. In addition to such interactions, CAFs and TAMs are also involved in a dynamic and reciprocal interrelationship with each other. Both CAFs and TAMs are capable of altering each other's functions. Here, the current understanding of the distinct mechanisms about the complex interplay between CAFs and TAMs are summarized. In addition, the consequences of such a mutual relationship especially for tumor progression and tumor immune evasion are highlighted, focusing on the synergistic pleiotropic effects. CAFs and TAMs are crucial components of the tumor microenvironment; thus, they may prove to be potential therapeutic targets. A better understanding of the tri-directional interactions of CAFs, TAMs and cancer cells in terms of tumor progression will pave the way for the identification of novel theranostic cues in order to better target the crucial mechanisms of carcinogenesis.

Gunaydin G 《Frontiers in Oncology》

Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1(+) TAMs.

Gok Yavuz B ，Gunaydin G ，Gedik ME ，Kosemehmetoglu K ，Karakoc D ，Ozgur F ，Guc D ... -  《Scientific Reports》

CXCL1-Mediated Interaction of Cancer Cells with Tumor-Associated Macrophages and Cancer-Associated Fibroblasts Promotes Tumor Progression in Human Bladder Cancer.

Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are reported to be associated with poor prognosis, depending on their pro-tumoral roles. Current knowledge of TAMs and CAFs in the tumor microenvironment of urothelial cancer of the bladder (UCB) is limited. Therefore, we investigated the paracrine effect induced by TAMs and CAFs in the tumor microenvironment of human UCB. For this, we first carried out immunohistochemical analysis for CXCL1, CD204 (TAM marker), αSMA (CAF marker), E-cadherin, and MMP2 using 155 UBC tissue samples. Next, CXCL1-overexpressing clones of THP-1-derived TAMs and NIH3T3-derived CAFs were developed by lentiviral vector infection. The immunohistochemical study showed high CXCL1 levels in UCB cells to be associated with enhanced recruitment of TAMs/CAFs, higher metastatic potential, and poor prognosis. Three-dimensional (3D) co-culture of UCB cells and TAMs/CAFs suggested that CXCL1 production in TAMs/CAFs play an important role in cell-to-cell adhesion and interaction among cancer cells and these stromal cells. CXCL1-expressing TAMs/CAFs enhanced tumor growth of subcutaneous UCB tumors in nude mice when injected together. In addition, an experiment using the orthotopic bladder cancer model revealed that CXCL1 production in TAMs/CAFs supported tumor implantation into the murine bladder wall and UCB growth when injected together, which was confirmed by clinical data of patients with bladder cancer. Thus, CXCL1 signaling in the tumor microenvironment is highly responsible for repeated intravesical recurrence, disease progression, and drug resistance through enhanced invasion ability. In conclusion, disrupting CXCL1 signaling to dysregulate this chemokine is a promising therapeutic approach for human UCB.

Miyake M ，Hori S ，Morizawa Y ，Tatsumi Y ，Nakai Y ，Anai S ，Torimoto K ，Aoki K ，Tanaka N ，Shimada K ，Konishi N ，Toritsuka M ，Kishimoto T ，Rosser CJ ，Fujimoto K ... -  《NEOPLASIA》

Cancer‑associated fibroblast‑induced M2‑polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor‑1 pathway.

Chen S ，Morine Y ，Tokuda K ，Yamada S ，Saito Y ，Nishi M ，Ikemoto T ，Shimada M ... -  《-》

Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages.

Takahashi H ，Sakakura K ，Kudo T ，Toyoda M ，Kaira K ，Oyama T ，Chikamatsu K ... -  《Oncotarget》