Continuous cellular division that is essential for the renewal of adult tissues, also provides recurrent opportunities for cancer development. However, it remains poorly understood how systemic tissue renewal leads to cancer formation. Planarians constantly renew their tissues and are susceptible to develop cancer-like phenotypes upon disruption of tumor suppressor genes (e.g. PTEN). PTEN is among the most commonly inactivated genes in human cancers, known to counteract the PI3K/AKT/TOR signaling cascade required for cellular proliferation, anti-apoptosis and growth. PTEN disruption in planarians is characterized by stem cell hyperproliferation and tissue colonization by abnormal cells, which rapidly kills the animal in roughly two weeks. In this study, we have catalogued the process of cellular transformation during tissue renewal and defined early and late stages (e.g. subcellular and cellular, respectively) of the PTEN phenotype in planarians. Our results indicate that early manifestation of cellular transformation in planarians have important similarities with cancer evolution in mammals. Furthermore, we can track pre-malignant abnormalities starting within 24-48 hours after PTEN disruption, which are attributed with DNA double stranded breaks, chromosomal abnormalities and checkpoint override. We have identified new genes and signaling pathways central to the regulation of cell cycle and DNA repair. Specifically, cell cycle checkpoint stability and DNA repair mechanisms; such as Rad54B and Rad51, respectively. Together, these signaling mechanisms facilitate the establishment and evolution of hallmarks of cancer (e.g. genomic instability, sustained proliferation and evasion of death) into the cancer-like phenotype. Our findings support the use of PTEN(RNAi) planarian model to obtain critical and new insights about cancer evolution during adult tissue renewal.