Radiation-induced inflammatory cascade and its reverberating crosstalks as potential cause of post-radiotherapy second malignancies.

The disease-free survival following radiotherapy is often limited by the development of second/secondary cancers. This significant impediment to effective cancer treatment implicated even in the modern-day radiotherapy needs to be countered effectively. Critical analysis reveals that besides achieving effective tumor control, radiotherapy elicits certain cellular and systemic inflammatory events in tumor infiltrate, which remain relatively stable and tend to facilitate "in-field" or "out of field" oncogenesis in due course of time. Acute pro-inflammatory cytokines generated as a result of radiation-induced oxidative insult and DNA damage induce genetic instability that contributes to tumor heterogeneity and plasticity. The reverberating crosstalks between radiation-targeted tumor and its microenvironment in turn initiate inflammatory loops that feedback the immune system to manifest as systemic consequences. An "inflammatory switchover" within the tumor microenvironment is thus induced by cumulative radiation exposure, initiating pro-tumor events that can severely limit the outcome of radiotherapy. Various pro-survival tumorigenic pathways activated as a result regulate radiation-induced hypoxia, ECM remodeling, angiogenesis/vasculogenesis, and immune suppression/evasion within the tumor microenvironment. NF-κB, HIF and STAT are identified as central regulating mediators among others that orchestrate inflammatory switchover from apoptosis-mediated tumor surveillance to radiation-induced carcinogenesis. Radiation-induced interleukins stimulate recruited macrophages and endothelial cells to promote intravasation, which is further aided by release of chemokines favoring extravasation and secondary site lesions. We hence propose that delineating the inflammatory signaling network emanating from irradiation of complex tumor tissue is critical for devising suitable therapeutic strategies to prevent post-radiotherapy second cancers or metastasis. Graphical Abstract ᅟ.