No description available.

No description available.

Sarcomatoid, or spindle cell squamous cell carcinoma (SCSC), is relatively uncommon, but may be encountered. It poses a challenge in differential diagnosis that includes other spindle cell neoplasms. We present a case where the lesion existed for 20 years and raised the potential of chronicity as a factor in inducing spindle cell morphology. Detailed immunohistochemical features are demonstrated, and discussion of the differential diagnosis is offered. The patient was an 89-year-old African-American female with an exophytic and polypoid mass of the right upper arm measuring 5.5 × 5.5 × 3.0 cm. The mass had been present for the last 20 years, and was gradually and very slowly increasing in size. After refusing surgery several times, she finally agreed to have an excision. The tumor proved to be SCSC.

Diss. (sammanfattning) Umeå : Univ., 2003. / Härtill 4 uppsatser.

published_or_final_version / Pathology / Doctoral / Doctor of Philosophy

published_or_final_version / Dentistry / Doctoral / Doctor of Philosophy

No description available.

No description available.

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science. Johannesburg, 2012 / Cell-extracellular matrix (ECM) detachment triggers a cell survival mechanism known as autophagy. A link between attachment and autophagy suggests a form of adhesion-based regulation, involving mechanotransduction of extracellular-originating signals to the cellular machinery controlling autophagy induction. This implies a role for integrin-linked kinase (ILK), which transmits mechanical stimuli to the mammalian target of rapamycin (mTOR) signalling pathway. Cells with a propensity for metastasis may negate these adhesive signals, inducing autophagy inappropriately. Metastasis is a hallmark of transformation frequently associated with human oesophageal squamous cell carcinoma (HOSCC). Additionally, hyperactive mTOR/mTORC1 signalling correlates increasingly with HOSCC. Therefore, the protein expression of significant signal transduction pathway intermediates was investigated in response to both soluble and ECM-originating stimuli. Measurements by SDS-PAGE and western-blotting coupled to semi-quantitative densitometry, during standard tissue culture conditions, revealed that HOSCC’s expressed moderate-to-high levels of mTOR, p-RPS6(Ser 235/236) and mATG-13; indicating elevated levels of autophagy induction despite aberrant signalling through mTOR/mTORC1. Additionally, an 80 kDa mTORβ isoform was identified in HOSCC cells with lower mTOR abundance, presumably to maintain aberrant mTORC1 signalling. A canonical role for the PI3K/PKB pathway was also identified; where autophagy induction accompanied diminished mTORC1 signalling in response to specific PI3K inhibition with LY294002 and serum withdrawal. However, autophagy induction varied in response to a dose-dependent decrease in mTORC1 signalling after exposure of HOSCC cells to rapamycin. Moreover, specific inhibition of p90RSK with BI-D1870, suggests that mTORC1 phosphorylates RPS6(Ser 235/236) in the absence of MAPK signals. Furthermore, ectopic ILK expression indicated an enhanced potential for adhesion-based signalling. Correspondingly, HOSCC cells commonly increased mTOR and p-RPS6(Ser 235/236) expression following growth on fibronectin or collagen. However, co-immunoprecipitation analysis revealed that signals transduction to mTOR precludes a direct interaction with ILK or FAK. Rather, ECM-modulation of mTOR occurs in a integrin-triggered, but PI3K-depedant manner; since specific inhibition of PI3K negated fibronectin-induced increases of mTOR concentration and RPS6(Ser 235/236) phosphorylation. Thus, these data strongly suggest mTOR is a target for adhesion-based signal transduction, where the ECM influences cell survival through mTORC1. Moreover, exploitation of autophagy induction post cell-ECM detachment in HOSCC may promote the survival of metastases during dissemination.

Previous data have unveiled a novel autoregulatory feedback loop between iASPP and p63 in the stratified epithelia; this involves two microRNAs, miR-574-3p and miR-720, and is critical for epidermal homeostasis. The iASPP oncoprotein, an inhibitory member of the ASPP (apoptosis stimulating protein of p53) family, is a key inhibitor of p53 and NF-κB and is highly expressed in many cancers. Non-melanoma skin cancer, comprising of cutaneous squamous carcinoma (cSCC) and basal cell carcinoma, is currently the most common malignancy in the UK. In view of this newly-identified iASPP-p63 axis, I hypothesised a potential role for dysregulation of this feedback loop in the pathogenesis of cSCC and aimed to assess the role of iASPP in human cSCC. Protein and mRNA expression patterns were assessed in a panel of 10 cSCC cell lines generated by our group. In addition, immunostaining of iASPP and p63 was performed in 107 cSCC clinical samples of variable differentiation status. The data reveal an overall increase in expression of iASPP and ΔNp63 in cSCC but also suggest a significant alteration of the cellular localisation of iASPP dependent on the differentiation status of the tumour. To further assess the effects mediated by the iASPP/p63 axis, iASPP and p63 have been silenced by RNAi technology in a subset of cSCC cell lines. Whilst data shows the direct effects of iASPP and p63 upon each other's expression are maintained in cSCC, epigenetic dysregulation of the feedback loop at the microRNA level may be occurring via a novel p63 regulator, miR-211-5p. Functionality of iASPP in cSCC (proliferation, apoptosis, cell motility/migration and invasiveness) provides evidence for a role of iASPP in preventing epithelial-mesenchymal transition in cSCC via a p63/miR-205-5. These findings provide potential future directions for development of clinical biomarkers and novel therapeutic targets for cSCC and may ultimately provide the tools for tackling the increasing morbidity and mortality associated with this malignancy.