Targeting Fusion Machinery Between Macrophages and Cancer Cells to Ameliorate Cancer Desmoplasia

Desmoplasia has been shown to exert mechanical forces and create a biochemical intra-tumoral immunity and influence the development and progression of a malignancy. Recent reports suggest a significant negative correlation between cancer patient survival and extracellular matrix deposition in primary tumors; and concomitant stromal targeting may enhance therapeutic outcomes in cancer patients.

In defining the source of the dense stroma, it is generally believed that over-activated CAFs could produce extracellular matrix (ECM) proteins, the major component of the dense stroma. Anti-fibrosis drugs including those depleting CAFs or collagen, sonic hedgehog inhibitor, antibodies against LOX/LOX2, were under clinical trials. However, CAF-depleted tumors displayed a more aggressive phenotype and alteration in regulatory T cells, raising the possibility that CAF-targeting strategies may have both beneficial and detrimental effects.

Considering the functional significance of macrophages in inflammation, desmoplasia, cancer initiation and progression, mounting studies had conducted to evaluate the efficiency of anti-macrophage as a novel strategy against cancer. Accordingly, the anti-macrophage strategies include the inhibition of the monocytes recruitment as well as transformation, and the ablation the macrophages directly. Given the multifaceted roles of maintaining homeostasis, the systemic depletion of macrophages may lead to increased infections or impaired ability of tissue-resident cells to carry out their normal function. Thus, the identification of tumor associated macrophage (TAM)-specific markers will enable the development of more sophisticated therapies that can be targeted specifically to tumors without affecting the function of other tissue-resident immune cells.

Recent studies had identified numerous factors such as platelet-derived growth factor (PDGF) and transforming growth factor b1 (TGFb1) released by TAMs, especially bone marrow (BM)-derived ones, involving in the process of activating CAFs. In addition, there were TAMs-derived pro-fibrotic factors, such as connective tissue growth factor (CTGF), chemokine ligand 17 (CCL17), CCL22 and reactive oxygen species (ROS). Similar observation was found in TAMs-derived matrix metallopeptidase 9 (MMP9) which involved in the stroma turnover by degrading the ECM proteins. However, rare study investigates the role of fusion between macrophages and cancer cells in desmoplasia and tumor progression as well as the strategy targeting fusion machinery of macrophages with cancer cells.

Several lines of evidence support that cell fusion between cancer cells and leukocytes, majorly macrophages, is one of the explanations for tumor resistance and progression. Recent genotyping of a metastatic melanoma to the brain that arose following allogeneic BM transplantation supports, first time clinically, fusion between a BM derived cell and a tumor cell playing a role in the origin of metastasis. Fusion hybrids enumerated in peripheral blood of pancreatic cancer patients were reported to correlate with disease stage and predict overall survival. Furthermore, general inflammatory responses were demonstrated to increase the number of fusion events. While the fusion events were demonstrated in animal and human, and were correlated with cancer resistance and metastasis, little is known regarding key questions such as the mechanisms through which macrophage-cancer cell fusion and subsequent genomic hybridization occurs in vivo; potential survival advantages of hybrids; reprogramming of fibrotic and immunologic tumor microenvironment by hybrids; and the development of novel strategies to target fusion machinery.