Bladder cancer can follow two mutually exclusive molecular pathways to tumorigenesis. The first pathway is often preceded by simple and papillary hyperplasia and exhibits a tumour morphology that is low-grade, superficial and papillary. Papillary carcinoma has a tendency to recur locally, but rarely invades and metastasizes. These tumors frequently harbour activating mutations in the H-Ras and fibroblast growth factor receptor (FGFR) 3 genes that constitutively activate the RTK-Ras pathway.
In contrast, the second tumor pathway is characterized by high-grade muscle-invasive tumours which either originate from flat carcinoma in situ (CIS)/severe dysplasia or arise de novo. These invasive tumors are characterized by loss-of-function mutations, affecting tumor suppressor genes including p53, RB and PTEN. Over 50% of these tumours progress to local and distant metastases. Certain cell cycle related molecules like p14ARF also contribute to the invasive form of the tumor through aberrant promoter hypermethylation.
Tumor environment is another contributing factor to invasion and metastases which is enhanced by aberrant expression of MMPs and angiogenic factors such as VEGF.