Molecular Mechanisms of Cancer, part II

Within a normal tissue, multiple anti-proliferative signals operate to maintain cellular quiescence and tissue homeostasis. Incipient cancer cells evade these anti-proliferative signals in order to prosper. Cancer cells also switch to different types, favoring only the ones that transmit pro-growth signals.  The WNT Signaling plays a central role in the development of many phylogenetically diverse organisms. Genetic alterations of components in the WNT pathway are commonly associated with melanomas and carcinomas of the breast and colon including the FAP (Familial Adenomatous Polyposis) syndrome. In the canonical WNT pathway GSK3Beta mediated Ctnn-Beta ubiquitination and degradation are inhibited by the binding of WNT1 (includes WNT1, WNT2, WNT3A, WNT8) to the receptor-coreceptor complex Fzd and LRP5/6. However WNT5A class (including WNT5A, WNT4, WNT11) inhibits binding of WNT1 to Fzd and LRPs. They ultimately lead to the activation Dsh that in turn inhibits GSK3Beta function. In the absence of WNT, Ctnn-Beta forms multiprotein complexes with Axinand APC, leading to its phosphorylation and degradation. With WNT stimulation, GSK3Beta activity is down modulated and unphosphorylated Ctnn-Beta then accumulates and translocates to the nucleus, to signal as a heterodimer with LEF/TCFproteins (Ref.3). The TCFs which bind and dimerize with Ctnn-Beta, along with LEF1, are TCF3 and TCF4. The “armadillo” repeats of free Ctnn-Beta also interacts with CdhE, Src (colon cancer), Ctnn-Alpha, p120Ctn and CBP. CdhEfunction is apparently lost in a majority of epithelial cancers. The disruption of CdhE/Ctnn-Beta-mediated gene transcription is caused by Cd2+ (Cadmium), SOX (Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome, Moebius Syndrome, myeloid leukemia, Acampomelic Campomelic Dysostosis, primary colorectal tumors, primary breast cancer, primary kidney tumors, and primary lung and prostrate cancer) and RAR (hepatocellular carcinoma) which further stimulates the development of tumors. Ctnn-Beta mutations are a crucial step in the progression of ovarian, hepatocellular, endometrial and prostrate cancers (Ref.3 & 4).

Several other genes not directly involved in WNT signaling but have overlapping functions with the canonical WNT pathway. Many of these genes are components of the Hedgehog pathway. The Hh-signaling comprises three main components: the Hh ligand; a transmembrane receptor circuit composed of the negative regulator Ptc, plus an activator, Smo a GPCR (G-Protein Coupled Receptor); and finally a cytoplasmic complex that regulates the Gli family of transcriptional effectors. Ptc, a twelve-pass membrane protein binds Hh ligand, and in the absence of ligand, Ptc interacts with and inhibits Smo. This repression culminates in a transcription factor, Gli acting as a transcriptional repressor. When Hh binds Ptc, its interactions with Smo are altered such that Smo is no longer inhibited. This leads to Gli protein entering the nucleus and acting as a transcriptional activator for the same genes it represses when Ptc is free to interact with and inhibit Smo. The processing and nuclear import of Gli is regulated via a complex of Gli with the cytoplasmic members of the Hh pathway, Fused (Fu) and SuFu (Suppressor of Fused). On Hh signaling, the complex is released from microtubules and full-length Gli enters the nucleus. In the absence of Hh signal, Fu and SuFu binding to Gli prevent Gli activation and retain it in the cytoplasm. Upon Hh reception, Fu is activated and acts on SuFu, alleviating their negative effect on Gli. As a result, Gli cleavage is reduced, Gli nuclear import overcomes its export and Gli is activated. Gli activation requires Fu to antagonize SuFunegative effect. Activated nuclear Gli is fully involved in the transcription of Hh target genes, like WNT, Ptc and BMPs. Mutations in the components of the Hedgehog pathway like Ptc, are responsible for the inherited cancer predisposition disorder known as Gorlin or Nevoid Basal Cell Carcinoma Syndrome (NBCCS), medulloblastoma, squamous cell carcinomas of the esophagus, transitional cell carcinomas of the bladder, and the benign skin lesions, trichoepitheliomas (Ref.4 & 5). However WNT signaling components like Dsh directly modulate the Notch signaling. The Notch COOH-terminal fragment NEXT is cleaved by Gamma-Secretase (Presenilin, PEN2, APH1 and Nicastrin) and TACE to release NICD into the cytoplasm. Upon release, the NICD translocates to the nucleus and associates with the RBPJ-Kappa, p300, HAT1 and HIF1Alpha which activate the expression of a set of target genes, including the HEY1/2, HES1 among others. This translocation is opposed by Numb and Dsh. HIF1Alpha gene regulation results in VEGF, Epo and PDGF expression and alterations in HIF1Alpha gene leads to sustained Angiogenesis for which it is often inhibited by different cellular levels of VHL (renal cell carcinoma, cerebellar hemangioblastoma). Consistent with the ability to influence cellular differentiation in multiple tissues, mutations of Notch receptors and components of its signaling pathway have been associated with a number of diseases, including human T-cell leukemia, CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), Spondylocostal Dysostosis, Alagille syndrome and breast carcinomas (Ref.6).