Phenotypic variations and chemosensitivity in small cell lung cancer

Furon, Emeline 2008. Phenotypic variations and chemosensitivity in small cell lung cancer. PhD Thesis, Cardiff University.

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Abstract

Many complex properties of cancer cells are effectively under selection within the in vivo microenvironment or following therapeutic insult. This critical combination of instability and shifting selection drives the heterogeneity of tumour cell populations in terms of many critical features. Small cell lung cancer (SCLC) is an aggressive, rapidly metastasizing neoplasm with an ability to develop resistance against chemotherapeutic agents. New SCLC therapeutic strategies are urgently needed that contain spreading disease without further compromising tumour chemosensitivity. Variants for attachment to tissue culture plastic of the NCI-H69 cell line, which grows in suspension but generates low frequency appearance of adhesion variants, were enriched, without prejudice for any specific extracellular matrix directed advantage, and then allowed for any proliferation/survival advantage in vitro to impact on the evolution of variation. Two sub-lines were generated representing two stages in variant enrichment. The developed SCLC model, which encompasses elements of variation and heterogeneity, provides opportunities to link in vitro behaviour of SCLC with in vivo characteristics with particular reference to the challenges faced in the management of SCLC such as the accrual of drug resistance. The variant model was characterized using microscopy, flow cytometry and microarray analysis, revealing variation in adherence and morphology impacting on SCLC behaviour, proliferative rate and polysialylation of the neural cell adhesion molecule. The microarray analysis has also revealed new cancer biomarkers that can be explored in clinic studies. This unique SCLC model was used to gain insights into links with chemoresistance. The studies revealed that the variant selection did not result in expansion of a drug resistant clone. Moreover, evidence of clonal evolution/selection was uncovered together with the finding of the absence of CSCs, even in enriched variants, as defined by the classical side population phenotype. The defined PSA expression patterns of the variants allowed for screening of carbohydrates-based agents for polysialylation knock-down.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
ISBN:	9781303196805
Date of First Compliant Deposit:	30 March 2016
Last Modified:	19 Mar 2016 23:30
URI:	https://orca.cardiff.ac.uk/id/eprint/54491

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