Basic cancer mechanisms and their variations in different cancer types. (a) Wnt signaling is constitutively activated in colorectal cancers by mutations in intracellular components (red). In renal, urothelial and prostatic carcinomas epigenetic downregulation of extracellular modulators (yellow) prevails. (b) HIF is constitutively activated by loss of hypoxia regulators in renal cancers (red). In other cancers, actual hypoxia or regulation by oncogenic signal transduction pathways (yellow) increase HIF expression or activity. (c) During progression of prostate cancer (and other cancer types), increased EZH2 activity enhances methylation at histone H3 lysine 27 (H3K27, red) and seems to precipitate DNA methylation at some target genes. An alternative mechanism leading to increased H3K27 methylation at some genes in renal cell carcinomas involves loss of histone demethylases, such as UTX (orange). (d) The two obvious histological subtypes of urothelial carcinoma are distinguished by different genetic alterations. Mutations and chromosomal changes predominating in papillary tumors (yellow) activate signal transduction pathways that ultimately drive cell cycle progression. In invasive carcinomas, mutations and chromosomal changes (red) inactivate proximate regulators of cell cycle progression and checkpoints. Positive influences are illustrated by arrows and negative influences by T-bars. Abbreviations: APC, adenomatous polyposis coli protein; CDKN, cyclin-dependent kinase inhibitor; Chr., chromosome; DKK, dickkopf homolog; DNMT1, DNA methyltransferase; E2F, transcription factor E2F; EGFR, epidermal growth factor receptor; EZH2, enhancer of zeste homolog 2; FGFR, fibroblast growth factor receptor; FH, fumarate hydratase; GSK, glycogen synthase kinase; HIF, hypoxia-inducible factor; H-RAS, Harvey rat sarcoma viral oncogene homolog; JMJD3, jumonji C domain-containing protein; LEF, lymphoid enhancer-binding factor; MAPK, mitogen activating protein kinase; mTOR, mammalian target of rapamycin; P14ARF, alternate reading frame product of the CDKN2A gene; p16INK4A, inhibitor of cyclin-dependent kinase 4; p21, cyclin-dependent kinase inhibitor p21CIP1; PHD, plant homeodomain homolog; PI3K/AKT, phosphatidylinositol 3-kinase/protein kinase AKT; PI3KCA, phosphatidylinositol 3-kinase p110 subunit alpha; RAS, rat sarcoma viral oncogene homolog; RB1, retinoblastoma 1; SDH, succinate dehydrogenase; SFRP, secreted frizzled-related protein; TCF, T-cell-specific transcription factor; TP53, tumor suppressor p53; UTX, ubiquitously-transcribed TPR gene on the X chromosome; VHL, von-Hippel-Lindau tumor suppressor; WIF, Wnt-inhibitory factor-1.