The PARP Enzyme Family and the Hallmarks of Cancer Part 2: Hallmarks Related to Cancer Host Interactions

SIMPLE SUMMARY: Members of the poly (ADP-ribose)-polymerase (PARP) enzyme family regulate a broad range of cellular functions related to carcinogenesis, tumor growth, cell death, replicative immortality, and metabolism. In the companion paper (part 1) to this review, we covered how the 17 members of the PARP1 family affect these intrinsic cancer cell hallmarks. Here, we explore the PARP association of cancer hallmarks that derive from tissue-level reorganization in tumors and interactions of cancer cells with the tumor stroma. Thus, the focus of this review will be on the roles played by PARPs in tumor invasion, metastasis, anticancer immune responses, and tumor-associated inflammation. We present mechanisms that may enhance or weaken the therapeutic efficiency of PARP inhibitors and discuss the potential targeting of non-DNA dependent PARPs. ABSTRACT: Poly (ADP-ribose) polymerases (PARPs) modify target proteins with a single ADP-ribose unit or with a poly (ADP-ribose) (PAR) polymer. PARP inhibitors (PARPis) recently became clinically available for the treatment of BRCA1/2 deficient tumors via the synthetic lethality paradigm. This personalized treatment primarily targets DNA damage-responsive PARPs (PARP1–3). However, the biological roles of PARP family member enzymes are broad; therefore, the effects of PARPis should be viewed in a much wider context, which includes complex effects on all known hallmarks of cancer. In the companion paper (part 1) to this review, we presented the fundamental roles of PARPs in intrinsic cancer cell hallmarks, such as uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, replicative immortality, and reprogrammed metabolism. In the second part of this review, we present evidence linking PARPs to cancer-associated inflammation, anti-cancer immune response, invasion, and metastasis. A comprehensive overview of the roles of PARPs can facilitate the identification of novel cancer treatment opportunities and barriers limiting the efficacy of PARPi compounds.