Deregulation of the Wnt signaling pathway can be found in many different human cancers. Changes in expression levels have been described for many components of the Wnt pathway. Overexpression of Wnt factors has been reported in several primary human malignancies including gastric cancer, head and neck squamous cell carcinoma, colon carcinoma, and chronic lym-phocytic leukemia (85-88). Several frizzled receptors have been found to be upregulated in esophageal, gastric, and colon cancers as well as in head and neck squamous cell carcinomas (86,87,89,90). The Wnt coreceptor LRP-5 has recently been reported to be overexpressed in osteosarcoma (91). Overexpression of dishevelled has been found in primary breast cancer, cervical squamous cell carcinoma, and mesothelioma (92-94). Also Frat1, which is supposed to be involved in the inhibition of GSK3P, has been described to be overexpressed in several primary human cancers including gastric, esophageal, pancreatic, cervical, and breast (85,95). However, the functional consequences of overexpression of several of these factors remains to be demonstrated.
In addition to upregulation of expression levels of activators of Wnt signaling downregulation of expression has been demonstrated for the secreted inhibitors of Wnt signaling sFRPs and WIF-1. sFRPs have been found to be downregulated in breast, bladder, and colorectal cancers as well as in mesothelioma (96-99). WIF-1 expression has been reported as being repressed in prostate, breast, lung, bladder, and colorectal cancers (100-102). Axin, which serves as the scaffold in the multiprotein complex facilitating phosphorylation of P-catenin, has been found to be biallelically mutated and hereby inactivated in a subset of hepatocellular and col-orectal cancers as well as in medulloblastoma (103-107).
Taken together, up to 90% of colorectal cancers harbor inactivating mutations in the APC tumor-suppressor gene or activating mutations of the proto-oncogene P-catenin. The tumor-suppressor gene APC is inactivated in the hereditary colorectal cancer syndrome familial adenomatous coli (FAP) (108,109). This inherited autosomal-dominant disease inevitably leads to the rise of hundreds to thousands of colorectal adenomas and if no proctocolec-tomy is performed, to the development of colorectal cancer. Although germline inactivating mutations of APC occur throughout the entire gene, somatic mutations are clustered in exon 15 between codons 1280 and 1500 (110). This results in a frame shift or a premature stop codon and a truncated protein. Mutations close to codon 1300 are mostly associated with allelic loss of the second allele of chromosome 5q, whereas tumors harboring a mutation outside this region tend to have a second truncating mutation (111,112). The APC gene product interacts with multiple proteins including P-catenin, axin, and GSK3p (51,52,113-116). Three different motifs of the APC protein are responsible for the regulation of P-catenin: three 15-amino acid (aa) P-catenin binding repeats, seven 20 aa P-catenin binding and downregulation repeats, and three repeats responsible for axin binding (113,117-120). Loss of one APC allele and truncation of the other results in the incapability to properly bind to axin and P-catenin and to form the multiprotein complex responsible for P-catenin phosphorylation (119,121). APC mutations can be detected in the earliest premalignant lesions of the colon and they are found as frequently in early adenoma as in invasive carcinoma arguing that mutation of APC is a critical step in colorectal carcinogenesis (122). Therefore, the APC tumor suppressor has been named the gatekeeper of the colon. Other human tumors that have been found to harbor APC mutations are melanoma, medulloblas-toma, and desmoids (114,123-127).
Mutation of one of the four serine or threonine residues in the destruction box or deletion of the whole box in the amino terminus prevents the phosphorylation and subsequent degradation of P-catenin. These molecular changes give rise to the cytoplasmic accumulation of P-catenin and after nuclear translocation, activation of P-catenin/Tcf transcription. P-catenin mutations are present in up to 50% of colorectal cancers with intact APC, adding up to approx 10% of all colorectal cancers harboring P-catenin mutations (128-132). In addition to colorectal cancers, P-catenin mutations have also been described in other gastrointestinal neoplasias including hepatocellular carcinoma and hepatoblastoma, gastric cancer, gastrointestinal carcinoids, and some rare nonductal pancreatic tumors (103,133-140). Other human cancers that have been found to contain P-catenin mutations include ovarian cancer, endometrial cancer, anaplastic thyroid carcinoma, prostate cancer, melanoma, medulloblastoma, and Wilms' tumor (123,132,141-149). For a comprehensive review of P-catenin mutations including mutation frequencies in various tumors see Giles et al. (150).
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