The role of myeloid CSF-1 receptor (CSF-1R) in mesothelioma cell proliferation

Colony-stimulating factor 1 receptor (CFS-1R) is a myeloid receptor with a key role in monocyte survival and proliferation. Its overexpression is associated with aggressive tumor characterized by a tumor microenvironment enriched of M2-like tumor-associated macrophages as well as drug resistance and poor prognosis. Recently, CSF-1R was detected on cancer cell surface in different solid tumors, capturing the interest of various research group interested in investigating the role of this receptor in non-myeloid cells. Malignant Mesothelioma is an aggressive tumor of the pleura and peritoneum, characterized by minimal clinical manifestations and few therapeutic options. Because the molecular mechanisms leading to mesothelioma carcinogenesis are unique and not fully understood, the tumor is difficult to tackle both diagnostically and therapeutically. Previous research demonstrated that CSF-1R is expressed by mesothelioma cells rather than normal mesothelial cells. Additional studies showed that CSF-1R activation induced mitogenic signaling pathways and the regulation of cell cycle-related factors in both monocytes and tumor cells. The aim of this thesis is to analyze how CSF-1R supported cancer cell proliferation and the investigation of the mechanisms regulating its expression throughout cell cycle phases. The expression of CSF-1R was investigated in different mesothelioma cell lines. Cell synchronization protocols were used to assess the expression of the receptor and its activity in the various cell cycle phases. Results indicated that CSF-1R expression characterized a pool of proliferating cells. We found that CSF-1R, different from other RTKs, undergoes a fine regulation during cell cycle progression. The percentage of CSF-1R+ cells increased in the G1 transition to S phase and in G2-M phase. Additionally, its inhibition negatively affected mitotic entry and G1-S phase transition. In terms of molecular mechanisms, using shRNA interference, we demonstrated that the Retinoblastoma protein (pRb) p105 is required for regulating CSF-1R expression in S-phase. Finally, we demonstrated that the overexpression of the receptor induced the activation of key intracellular pathway promoting cell proliferation including ERK5, ERK1/2 and AKT signaling. Collectively these data described a unique characteristic of CSF-1R which is differentially expressed during cell cycle phases, indicating a fine tuning throughout cell cycle. These findings extend our understanding of CSF-1R role in malignancies, making it a suitable target for an anti-cancer therapy. Further studies are required to evaluate the potential impact of targeting CSF-1R and better understand the mechanisms controlling its activity in cancer.