Oncogenic Metabolism Acts as a Prerequisite Step for Induction of Cancer Metastasis and Cancer Stem Cell Phenotype

Figure 1

DNA damage-induced senescence plays important roles in cancer development. DNA damage is induced by replication stress/telomere erosion, oxidative stress, and oncogene activation, which activate DNA damage response (DDR). DDR induces transient cell cycle arrest, apoptosis, and cellular senescence. DDR is mediated by checkpoint kinases ATM and ATR, which induce p53. In DDR, p53 induces the expression of many proapoptotic proteins including the BCL2 family (BAX, BID, PUMA, and NOXA) to induce apoptosis. In addition, p53 induces the expression of p21 which in turn activates RB tumor suppressor. p53, p21, and RB are involved in transient cell cycle arrest and cellular senescence. The p53-mediated cell cycle arrest, apoptosis, and cellular senescence act as tumor suppressive processes. Under transient cell cycle arrest, DNA damage is repaired by diverse DNA damage repair mechanisms. However, extensive DNA damage or insufficient repair by inactivation of DDR leads to genomic instability, then tumor-promoting growth factor (TPGF) and hypoxia contribute to cancer development and tumor progression. Senescent cells secrete senescence-associated secretory phenotype (SASP) proteins, consisting of growth factors, immunomodulatory chemokines and cytokines, extracellular matrix- (ECM-) remodeling proteases (matrix metalloproteinases), and ECM/insoluble proteins. The secreted cytokines induce an immune response. In addition, damaged DNA is recognized as a damage-associated molecular pattern (DAMP), triggering an immune response. Immune response inhibits cancer development at early stages, whereas it promotes cancer development at later stages. Furthermore, senescent cells exhibit increased glycolysis, which is regulated by the counterbalance of p53 and RB. Finally, SASP induces EMT, invasion, metastasis, and angiogenesis that are crucial for tumor progression.