SPINK1 and cancer: HIF-1α promotes ATP metabolism, and p53 activation and stimulates EC survival, thereby mediating the ultimate cancer radiation responses.382,383 The serine peptidase inhibitor Kazal type 1 (SPINK1) is secreted in a HIF-dependent paracrine manner to reduce radiation-induced DNA damage and enhance radiation resistance in adjacent cancer cells through EGFR and nuclear factor erythroid 2-related factor 2 (NRF2).384 Radiation-induced EC death leads to secondary tumor cell killing.385 The vascular system also affects radiation therapy.