Posters: J Stem Cell Res Ther
Spatio-temporal cues defined for certain critical components in a particular developmental pathway provide a firm basis for detecting the order, hierarchy and ?switching-off or on? of genes that regulate it. The various time-points at which genes are switched ?on/off? determines the fate of how a cell behaves in terms of being functional or non-functional, due to disruption of that specific pathway. This piece of work reports a strong evidence, toward identifying such components (associated with Wntsignaling) which indeed determine the transformation of a ?blank-slate? (?cells of origin? and/or putative ?cancer stem cells?) or ?primitive-state? epithelial cells to an intermediate adenoma/polyp (dyspastic), and later to a proliferative (hyperplastic) or cancerous (neoplastic) state/s. The report discusses a critical temporal requirement of Caesin-Kinase I (CKI) and Human-Discslarge (hDlg), which have been identified as ?early? and ?late? acting molecules respectively, in a very crucial developmental event, that basically transforms ?polyps? to full-fledged ?carcinomas? (epithelial cancers) in Colorectal(CRC) tumors. A concomitant loss of CKI protein, in cells mutant for APC, a tumor suppressor gene, basically initiates the process of early-late polyposis, which furthers the progression of tumorigenesis, to finally give rise to confluent malignant cancers. The disturbance of architectural properties during metastasis, owing to the loss of apico-basal polarity of cells, consequently perturbs the hDlg protein expression, since it is basically a membrane associated protein, belonging to the MAGUK (Membrane-Associated- Guanylate-Kinase) family. The loss of a critical cytoplasmic-component of APC protein, which most prominently disappears in cells mutant for APC, actually governs the early loss of expression of CKI during polyposis and consequently hDlg in later stages of colorectal carcinoma development. The detection of this vital parameter, served as a focal-point and the most striking diagnostic feature, for detection of effects, i.e., gain/ loss of other downstream components of Wnt-pathway, involved during the progression of CRC disease. The results presented here, prove that apart from being associated with each other as bindingpartners during Wnt-signaling, the loss of CKI and APC, together, is indeed responsible for triggering the normal epithelial cells of intestinal lining, to polyps followed by an awry late/confluent cancerous state, where hDlg expression also gets aberrant, due to subsequent loss of architectural properties in these abnormal cancer cells. Coincidentally, the chromosomes on which these genes reside have been found to be dense and rich in SNPs (hot-spots), the details of which have been recently discussed in a separate report.
Jyoti Bhojwani is presently a Faculty of Genetics/Bioinformatics/ Principal Investigator of the MTech Research Programs (Bio-Informatics) at University of Indore, India. She obtained her BSc (Bachelors degree) in Biological Sciences/Chemistry/Physics, MSc (Master?s degree) in Life-Sciences, and Doctoral degree (PhD) at School of Life-Sciences, University of Indore. She pursued her Post-doctoral ventures at Max-Planck Institute for Biophysical Chemistry (FRG), University of California-Irvine and University of Pittsburgh (USA). Currently, her projects mainly focus on translational-research and extrapolation of basic developmental mechanisms from model-systems like fruitfly (Drosophila) to human. She is keen on studying in details the genetic factors, which presumably aid in understanding of mechanism by which ?cancer stem cells? function in transforming a tissue from normal to cancerous states. Her research has a motive to further facilitate the perception of stem cell potential/mechanistic in areas of regenerative medicine, translational research and anti-cancer therapy.