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Worthley D.L.,Research Foundation Clinical Research Center | Worthley D.L.,Queensland Institute of Medical Research | Giraud A.S.,Murdoch Childrens Research Institute
Cancer Microenvironment | Year: 2010

The extracellular components of the cancer microenvironment play a critical role in tumor initiation, progression and invasion. In this review we examine the normal formation and function of the basement membrane and extracellular matrix. We characterize the interactions between the matrix and the epithelium and explore the causes and consequences of the extracellular remodeling that accompanies carcinogenesis. Finally, we address the therapeutic possibilities of incorporating matrix as well as epithelial strategies in the management of digestive cancer. © 2010 Springer Science+Business Media B.V.


Worthley D.L.,Research Foundation Clinical Research Center | Worthley D.L.,Queensland Institute of Medical Research | Giraud A.S.,Murdoch Childrens Research Institute
Cancer Microenvironment | Year: 2010

The normal gastrointestinal stroma consists of extra-cellular matrix and a community of stromal cells including fibroblasts, myofibroblasts, smooth muscle cells, pericytes, endothelium and inflammatory cells. α-smooth muscle actin (α-SMA) positive stromal fibroblasts, often referred to as myofibroblasts or activated fibroblasts, are critical in the development of digestive cancer and help to create an environment that is permissive of tumor growth, angiogenesis and invasion. This review focusses on the contribution of activated fibroblasts in carcinogenesis and where possible directly applies this to, and draws on examples from, gastrointestinal cancer. In particular, the review expands on the definition, types and origins of activated fibroblasts. It examines the molecular biology of stromal fibroblasts and their contribution to the peritumoral microenvironment and concludes by exploring some of the potential clinical applications of this exciting branch of cancer research. Understanding the origin and biology of activated fibroblasts will help in the development of an integrated epithelial-stromal sequence to cancer that will ultimately inform cancer pathogenesis, natural history and future therapeutics. © 2010 The Author(s).


Worthley D.L.,Research Foundation Clinical Research Center | Worthley D.L.,Queensland Institute of Medical Research | Whitehall V.L.J.,Research Foundation Clinical Research Center | Whitehall V.L.J.,Queensland Institute of Medical Research | And 16 more authors.
Oncogene | Year: 2010

There are two major molecular pathways to sporadic colorectal cancer, the chromosomal instability (CIN) and the CpG island methylator phenotype (CIMP) pathways. This study recruited 166 patients undergoing colonoscopy. Biopsy samples were collected from the cecum, transverse colon, sigmoid colon and rectum. DNA methylation was quantified at type A (ESR1, GATA5, HIC1, HPP1, SFRP1) and type C markers (MGMT, MLH1, CDKN2A, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. Type A genes are frequently methylated in normal and neoplastic tissues, proportional to tissue age. Type C methylation is more specific for neoplasia. The last five type C markers comprise a CIMP panel. The mean type A and CIMP-panel methylation Z-scores were calculated. In all, 88 patients had adenomatous lesions, 32 had proximal serrated polyps (PSPs) and 50 were normal. Most type A genes showed direct correlations between methylation and age (ESR1, 0.66, P0.0001), with higher methylation distally (ESR1, P0.0001). On multivariate analysis, type A methylation was inversely associated with colorectal adenomas (odds ratio0.23, P0.001), the precursor to CIN cancers. CIMP-panel methylation was significantly associated with advanced PSPs (odds ratio5.1, P0.009), the precursor to CIMP cancers. DNA methylation in normal mucosa varied with age and region and was associated with pathway-specific pathology. In the future, the colorectal field could yield important information and potentially inform clinical practice. © 2010 Macmillan Publishers Limited All rights reserved.

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