Figure 4. HCMV effects during carcinogenesis.

Cancer predisposing risk factors are known to cause cellular injury, which in turn activates normal inflammatory response. HCMV can be reactivated as the latently infected monocytes differentiate into macrophages during migration as a part of this inflammatory response. The classically activated macrophages (M1) carrying a re-activated virus infection, can then infect other cell types, such as fibroblasts, endothelial and epithelial cells, which are more permissive to lytic HCMV infections. HCMV infected cells promote inflammatory and angiogenic secretome, that paracrinally, by intercellular signaling through secretion of cytokines, such as IL-6, TGFβ, GM-CSF and cmvIL-10, induce haemangiogenesis, lymphangiogenesis, cell proliferation as well as immune evasion/immunosupression. HCMV infection in the epithelial cells is evidenced to cause transformation to tumor cells [69]. The presence of HCMV infection in the tissue macrophages (M1) or secretion of GM-CSF by the tumor cells can result in activation of M2 macrophage differentiation pathway. Presence of M2 macrophages favor a pro-tumoral microenvironment due to their matrix-remodeling and anti-inflammatory properties [110, 111]. These immunosuppressive M2 macrophages display a phenotype that is closely related to tumor-associated macrophages (TAMs), of which presence in the tumors is known to play an important prognostic value. In addition, tumors contain a subpopulation of cancer cells, called cancer stem cells or tumor initiating cells (TICs), that have undergone an epithelial-mesenchymal transformation (EMT). The close vicinity of TAMs and cancer cells undergoing EMT at the invasive front of tumors, suggests that these cell types might interact mutually [5, 102]. The TAM-like macrophage phenotype secretes CCL5 stimulating EMT and migration of the cancer cells, and thereby increases the invasiveness and metastasis of the tumor [127]. Despite the transformation and tumor forming process involving epithelial cells, TAMs, TICs, endothelial cells and cancer associated fibroblasts (CAFs), the HCMV infection contributes to disarm the NK cells and adaptive immune responses (see Figure 2). NK cells activation of the cytotoxic T-cell responses displays a crucial function in the cell-mediated first-line host responses against viral infections and cancer initiation [128–130]. NK cells are also involved in antibody-dependent cellular cytotoxicity by B cell activation through CD4+ T cells [120].