No description available.

Tiam1 (for T-lymphoma invasion and metastasis-inducing protein) belongs to the Rho GEF family of proteins. In response to growth factors and cell-substrate interactions, Tiam1 selectively activates Rac. Using a two stage chemical carcinogenesis protocol (DMBA/TPA) it was previously shown that mice lacking Tiam1 are resistant to the development of Ras-induced skin tumours, suggestmg an important role for Tiam1/Rac signalling in tumourigenesis in vivo.

No description available.

No description available.

IKK[alpha] is a 85KD serine/threonine protein kinase and a subunit of the IKK complex, which contains IKK[alpha], IKK[beta], and IKK[gamma]. IKK[alpha] and IKK[beta] are highly conserved and they contain three functional domains of kinase domain, leucine zipper (LZ), and helix-loop-helix (HLH). Although IKK[alpha] and IKK[beta] can phosphorylate IκB proteins in vitro, IKK[alpha] and IKK[beta] have distinct physiological functions during mouse development. Genetic studies showed that IKK[alpha] is essential for embryonic skin development in mice. Mice deficient in IKK[alpha] display a hyperplastic epidermis that lacks terminal differentiation, resulting a death soon after birth because of the severely impaired skin. Recently, we reported a reduction in IKK[alpha] expression and identified somatic Ikk[alpha] mutations in a high proportion of poorly differentiated human squamous cell carcinomas (SCCs) (Liu et al., 2006). The aim of this study is to investigate the novel role of IKK[alpha] in skin carcinogenesis. We firstly examined IKK[alpha] expression and Ikk[alpha] mutations in human SCCs and found a reduction of IKK[alpha] in poorly differentiated human SCCs and identified somatic Ikk[alpha] mutations in exon 15 of Ikk[alpha] in human SCCs. We then examined the susceptibility of Ikk[alpha] hemizygotes to chemical carcinogeninduced skin carcinogenesis. In this chemical carcinogen-induced skin carcinogenesis setting, 7,12-dimethylbenz[a]anthracene (DMBA) induces Ras mutations and 12-Otetradecanoyl-phorbol-13-acetate (TPA) promotes Ras-initiated cell proliferation. We found two times more papillomas and eleven times more carcinomas in Ikk[alpha superscript +/-] mice than in Ikk [alpha] superscript +/+] mice induced by DMBA/TPA. Ikk[alpha superscript +/-] mice developed larger and earlier tumors than did Ikk[alpha superscript +/+] mice. Poorly differentiated carcinomas expressed low levels of IKK[alpha]. Ninety five percent of the Ikk[alpha superscript +/-] carcinomas and 44% of the Ikk[alpha superscript +/-] papillomas lost the remaining wild type Ikk[alpha] allele. This result indicates that the remaining one wild type Ikk[alpha] allele is important for preventing malignant carcinoma conversion. Also Ikk[alpha] mutations were detected in these skin tumors. Reduced IKK[alpha] was found to enhance TPA-induced mitogenic and angiogenic activities in mouse skin. Taken together, these results suggest that reduction of IKK[alpha] expression provides a selective growth advantage, which cooperates with DMBA-initiated Ras activity to promote skin carcinogenesis. In addition, we observed a small group of FVB female Ikk [alpha superscript +/-] mice for 1.5 years and found that 12/ 24 mice developed various spontaneous tumors including mammary gland carcinomas, uterine and ovary tumors, and dermal fibrosacomas. Somatic Ikk[alpha] mutations, elevated IKK/ NF[subscript -k]B and extracellular signal-regulated kinases (ERK) activities and elevated cyclin D1 levels were detected in these spontaneous tumors. These results suggest that these molecular alterations may contribute to the development of these tumors although the precise role of the down-regulation of IKK in the development of the tumors remains to be determined. Overall, our data and other published results suggest that IKK[alpha] is a new tumor suppressor in men and mice. / text

No description available.

No description available.

No description available.

There is an urgent need to define the key pathological driving events in human cutaneous squamous cell carcinoma (cSCC) in order to identify novel therapeutic targets. Already the second most common form of human non-melanoma skin cancer, the incidence of cSCC has continued to rise at epidemic proportions over the past two decades. Rarely, cSCC can be highly aggressive, causing significant soft-tissue defects in sun-exposed areas of skin and progressing to metastatic disease, which is usually associated with poor survival. The transforming growth factor-β (TGF-β) signalling pathway is known to play key regulatory roles in skin homeostasis and wound repair. Murine studies indicate that loss of TGF-β signalling is sufficient to drive cSCC, but conclusive evidence for a similar role in human cSCC remains elusive. Combining immunohistochemical and genetic studies of the TGF-β signalling pathway on human cSCC tissue, with a thorough examination of TGF-β responses in human primary cSCC cell lines in-vitro, this thesis aims to investigate the complex role of TGF-β signalling in human cSCC. An extensive tissue micro-array analysis demonstrated the consistent reduction of endogenous TGF-β signalling activity in human primary cSCC. This intriguingly correlated with higher risk thick tumours pathologically, indicating that TGF-β is likely to act primarily as a tumour suppressor in human cSCC and its reduction or loss may impart a significant growth advantage for cSCC tumour cells. This tumour suppressor effect was reflected in-vitro, whereby the majority of primary cSCC cell lines remained sensitive to TGF-β mediated growth arrest. Resistance to TGF-β tumour suppression was also identified, and mechanistically its main protagonist in cSCC cell lines appeared to be mutational loss of TGF-β receptors. Consolidating in-vitro findings, both whole exome sequencing and 454 pyrosequencing of human cSCC tissue revealed frequent functionally damaging mutations of both TGF-β type 1 and type 2 receptors, indicating that mutational loss of the TGF-β pathway may be a key driving event in human cSCC tumourigenesis. Perhaps most interestingly, mutational loss of TGF-β type 2 receptors in cSCC cell lines appeared to result in a novel pro-oncogenic dependence on TGF-β type 1 receptor kinase activity, highlighting not only the important paradoxical role of TGF-β mediated tumour promotion in cSCC, but also the potential for signalling crosstalk between alternative TGF-β superfamily members, namely Activin signalling, to drive tumourigenesis in the absence of active TGF-β signalling. Although further mechanistic studies are required to support this hypothesis, the mutational status of TGF-β type 2 receptors may not only provide a powerful prognostic tool for patients with cSCC, but also represent an important biomarker for the targeted use of TGF-β inhibitors in potentially aggressive disease where pro-tumourigenic responses could be driving disease progression.

Skin cancer is the most common form of cancer and it is on the rise. If skin cancer is diagnosed early enough, the survival rate is close to 90%. Oblique-incidence diffuse reflectance (OIR) spectroscopy offers a technology that may be used in the clinic to aid physicians in diagnosing both melanoma and non-melanoma skin cancers. The system includes a halogen light source, a fiber optic probe, an imaging spectrograph, a charge coupled device (CCD) camera, and a computer. Light is delivered to the skin surface via optical fibers in the probe. After interacting with the skin, the light is collected and sent to the spectrograph that generates optical spectra. Images and histopathological diagnoses were obtained from 250 lesions at the University of Texas M.D. Anderson Cancer Center (Melanoma and Skin Center). To classify OIR data, an image processing algorithm was developed and evaluated for both pigmented and non-pigmented lesions. The continuous wavelet transform and the genetic algorithm were employed to extract optimal classification features. Bayes decision rule was used to categorize spatiospectral images based on the selected classification features. The overall classification accuracy for pigmented melanomas and severely dysplastic nevi is 100%. The overall classification accuracy for non-pigmented skin cancers and severely dysplastic nevi is 93.33%. Oblique-incidence diffuse reflectance spectroscopy and the developed algorithms have high classification rates and may prove useful in the clinic as the process is fast, noninvasive and accurate.