Sheets of highly organized epithelial cells line all the cavities and freesurfaces of the body, forming barriers that control the movement of liquidsand cells in the body organs. The organized structure of normal breastepithelial cells may also serve as a barrier against cancer, according to astudy by University of Helsinki scientists.
The work appears this week inthe online edition of the Proceedings of the National Academy of Sciences(PNAS).
Finnish researchers found that the tightly organized architecture ofmammary epithelial cells is a powerful restraint against the cancer geneprovoked inappropriate proliferation. Their study also links function of atumor suppressor gene to the development of cancer gene resistant epithelialorganization.
“Rogue cancer genes can force epithelial cells to proliferateand proliferation of malignant cells will certainly disrupt the organizedepithelial structure. However, there has always been this chicken or the eggproblem: Does cancer gene initiate cell proliferation, which causesdisruption of the epithelial structure or does loss of tissue structure comefirst, creating suitable environment for cancer genes to enforce the cellcycle progression”” explains the research team leader Juha Klefstrom, Ph.D.The present study supports the idea that loss of tissue structure comesfirst.
Experiments with fly models have shown that loss of epithelial organizationcan enhance the tumorigenic potential of cancer genes (oncogenes) and thesefindings prompted Juha Klefstrom’s team to explore whether the formation ofepithelial organization works other way around and suppresses oncogenefunction. “We were amazed to find out that the formation of organizedmammary epithelial architecture in three-dimensional organotypic cellculture correlated with complete loss of oncogenic activities of c-Myccancer gene” says Klefstrom.
Johanna Partanen, a graduate student in Klefstrom’s laboratory and leadauthor in the article, continues “We also asked how to dismantle theproliferation resistance of the epithelial organization. To find clues togenes involved in the development of organized epithelial structure, weturned back to fly”. Epithelial cells of both flies and humans livetheir lives in the companionship of others, held together by tight belt ofadhesion proteins and interactions with supporting extracellular matrix.Developmental geneticists working with fly models have identified animportant group of genes, PAR genes, which regulate the development ofhighly ordered epithelial cell organization. “Most interesting candidatefor us was LKB1, the human homologue of Par4 protein, because this gene hasstrong connection to human epithelial disorders” says Partanen. Previousresearch done by Akseli Hemminki, Lauri Aaltonen and Tomi M?kel? at theUniversity of Helsinki has linked this gene to Peutz-Jeghers cancerpredisposition syndrome and it has also been suggested that LKB1 has tumorsuppressor functions in several epithelial cancers. Klefstrom’s team foundthat epithelial cells missing the LKB1 protein are able to form onlycancer-like disorganized epithelial structures. This disorganized environment enables c-Myc oncogene to drive inappropriate cell proliferation.
The study demonstrates that organized epithelial structure can suppressmalignant actions of cancer genes and identifies LKB1 tumor suppressor geneas an architect of this proliferation resistant organizational plan. Theordered structure of epithelial cells is frequently lost in epithelialtumors, like breast carcinoma, and the study suggests that loss of structuremay play more active role in progression of tumors than previouslyanticipated.