The integrity of circulating DNA, measured as the ratio of longer to shorter DNA fragments, is higher in cancer patients than in normal individuals . Apoptotic
cells release DNA fragments that are usually 185 to 200 base pairs selleck in length. Uniformly truncated fragments of DNA (and RNA) are produced by a programmed enzymatic cleavage process during apoptosis . As we and other groups have reported, methylation of tumor suppression genes detected in circulating DNA is associated with prognosis . We speculate that the high rate of unscheduled cell death in the tumor microenvironment elevates nucleic acid DAMPs. Elevated levels of nucleic acid DAMPs and other DAMPs might foster chronic inflammation, a hallmark of the tumor microenvironment. Figure 3 shows how interactions between TLRs and DAMPs could create and maintain a self-perpetuating tumor microenvironment. In this microenvironment, cancer cell death might stimulate cancer progression if nucleic acid fragments released by the dead tumor cells are transfected into normal cells, thereby changing the normal cell’s properties. Normal cells in the tumor microenvironment might also be transfected by microRNA released from tumor cells, because these small
RNA molecules (20–22 base pairs) are easily taken up by cells. Horizontal mediated transfection of microRNA and mRNA in mammalian cells is an intriguing possibility but has yet to be demonstrated Peptide 17 in vivo. This phenomenon could explain the expression of tumor-related proteins by normal cells in the tumor microenvironment. Fig. 3 During cancer growth and unscheduled cell death, DAMPs derived from necrotic cancer cells might continuously activate TLRs and create a chronic inflammatory condition as well as PAMPs. TLR ligation activates NF-κB and MAPK signaling, causing the production of proinflammatory cytokines
and chemokines. The resulting aberrant molecular pattern of cytokines/chemokines might have a crucial role in immunotolerance, maintain tumor microenvironment, tumor angiogenesis that supports tumor progression Fossariinae TLR-targeted Therapies Because several TLRs can induce strong anti-tumor activity by regulating the functions of immune cells that infiltrate the tumor microenvironment, clinical trials are investigating novel anticancer therapies based on TLR ligand delivery. A successful example is imiquimod. This TLR7 agonist is used extensively to treat actinic keratosis and basal cell carcinoma, and it is being studied as an adjuvant therapy for melanoma. A study of imiquimod 5% cream in 90 patients with basal cell carcinoma reported a 96% clearance rate, and only two recurrences during application a mean follow-up period of 36 months. Cutaneous side effects were minimal; there were no systemic side effects .