Date Published: May 8, 2017
Publisher: Public Library of Science
Author(s): Meike de Wit, Beatriz Carvalho, Pien M. Delis-van Diemen, Carolien van Alphen, Jeroen A. M. Beliën, Gerrit A. Meijer, Remond J. A. Fijneman, Dragana Nikitovic-Tzanakaki.
One prominent event associated with colorectal adenoma-to-carcinoma progression is genomic instability. Approximately 85% of colorectal cancer cases exhibit chromosomal instability characterized by accumulation of chromosome copy number aberrations (CNAs). Adenomas with gain of chromosome 8q, 13q, and/or 20q are at high risk of progression to cancer. Tumor progression is also associated with expansion of the extracellular matrix (ECM) and the activation of non-malignant cells within the tumor stroma. The glycoproteins versican and lumican are overexpressed at the mRNA level in colon carcinomas compared to adenomas, and are associated with the formation of tumor stroma.
The aim of this study was to characterize versican and lumican protein expression in tumor progression and investigate their association with CNAs commonly associated with adenoma-to-carcinoma progression.
Tissue microarrays were constructed with colon adenomas and carcinomas that were characterized for MSI-status and DNA copy number gains of chromosomes 8q, 13q and 20q. Sections were immunohistochemically stained for lumican and versican. Protein expression levels were evaluated using digitized slides, and scores were finally dichotomized into a positive or negative score per sample.
Lumican and versican expression were both observed in neoplastic cells and in the tumor stroma of colon adenomas and carcinomas. Lumican expression was more frequently present in epithelial cells of carcinomas than adenomas (49% versus 18%; P = 0.0001) and in high-risk adenomas and carcinomas combined compared to low-risk adenomas (43% versus 16%; P = 0.005). Versican staining in the tumor stroma was more often present in high-risk adenomas combined with carcinomas compared to low-risk adenomas (57% versus 36%; P = 0.03) and was associated with the presence of gain of 13q (71% versus 44%; P = 0.04).
Epithelial lumican and stromal versican protein expression are increased during colorectal adenoma-to-carcinoma progression.
Colorectal cancer (CRC) develops in a multistep process that starts with the formation of a colon adenoma. These are benign lesions arising from the intestinal epithelium, of which only a small subset progresses into CRC [1,2]. The progression of normal colon epithelium to invasive CRC is accompanied with (epi)genetic changes that cause alterations in cellular processes resulting in tumorigenic capacities . Specific gains and losses of (parts of) chromosomes are associated with adenoma-to-carcinoma progression , and these include gains of 20q, 13q and 8q . These chromosomal aberrations are considered non-random events that drive adenoma-to carcinoma progression [6–8].
Lumican and versican are proteins relevant to the biology of cancer and their expression was found to be associated with clinical outcome. The present study aimed to explore the role of these proteins in the pathogenesis of CRC, and more explicitly their association with adenoma-to-carcinoma progression. To this end, expression levels of lumican and versican were explored in a series of 82 colorectal adenomas and 82 carcinomas. The expression of lumican was more prevalent in epithelial cells of CRCs than of adenomas. Versican staining was more often observed in the stroma of high-risk adenomas and carcinomas combined compared to low-risk adenomas. Although previous work revealed higher mRNA expression levels of the LUM and VCAN genes in carcinomas compared to adenomas, we did not observe significant correlations between mRNA and protein levels. Various post-transcriptional regulation mechanisms can lead to lack of correlation between mRNA expression levels and protein levels . Alternatively, the absence of mRNA-protein correlation might also be explained by technical limitations of immunohistochemical stainings, which is a semi-quantitative rather than a quantitative read out of biology. Moreover, it is unknown what proportion of secreted lumican and versican is locally captured by the (tumor) tissue and still can be visualized by immunohistochemistry.