The colorectal cancer (CRC) is the second leading causes of cancer-related deaths worldwide. It results from a progressive accumulation of genetic and epigenetic alterations that lead to uncontrolled growth of colonocytes from non-cancer polyps into invasive cancerous lesion. A present estimate is that between 15-30% of CRC cases may have a major hereditary component while the 70-85% of CRC cases are sporadic and the patients have no identifiable genetic risk factors. The huge spectrum of somatic alterations that contribute in sporadic CRC development have been identified in mutations of oncogenes and tumor suppressor genes, such as Wnt/ß-catenin, K-ras, TP53, TGFß, BRAF, etc..
Intriguingly, the ligand-induced Notch signalling has been implicated in various aspects of cancer biology and its role in regulating the intestinal development and homeostasis has already been identified. In fact, several studies demonstrate that alterations of Notch pathway contribute to the CRC onset and malignancy. In particular, it has been suggested that the specific Notch ligand Jagged1 is aberrant expressed in about 50% of human colon tumors and some studies correlate the levels of Jagged1 expression with tumor differentiation parameters and stage of CRC.
We have observed that in several CRC cell lines the ligand Jagged1 is not only abundantly overexpressed but it undergoes to a constitutive processing that ends in the generation of a soluble intracellular domain (Jag1-ICD) capable to move into the nucleus. In this cellular compartment, Jag1-ICD could be involved in regulation of some transcriptional factors empowering the aggressiveness of CRC cells. Thus, the pharmacological blockage of Jagged1 intracellular processing inhibits both the migration ability of CRC cell lines and their proliferation rate.
We aim to better understand the molecular mechanism responsible of such effects Jagged1 dependent in CRC in order to be able to define a new potential target therapy.
Several studies have carefully analysed the progression of non-cancer polyps into invasive cancerous lesions, but the molecular pathogenesis as well as the ontogenesis of this neoplasm is not still completely understood. In fact, despite substantial advances in knowledge of the molecular mechanisms involved in colorectal cancer development and progression, this disease still remains one of the leading causes of cancer-related deaths in the world and the median overall survival of metastatic CRC patients is less than 5 year. CRC has a poor prognosis and is resistant to standard and advanced chemotherapeutic protocols, for this reason CRC treatment is a medical, economic and social emergency that has to be urgently faced.
Recently, Jagged1 has been observed to be significantly up-regulated in CRC patients with poor prognosis and to play an important role in maintaining/promoting CRC disease.
Starting from these initial observations and our preliminary results, we believe that Jagged1-ICD constitutively activated may significantly contribute to the development of CRC, conferring selective advantage to cancer-initiating cell or initiated tumor cell to drive the transformation and tumorigenic progression of colonic epithelial cells.
In this project we propose to perform in vitro and in vivo studies and we expect to obtain results that may shed light on the Jagged1-ICD-dependent molecular events that may be involved in CRC progression through the regulation of the main cellular functions associated with tumorigenesis, such as apoptosis, proliferation and cell migration.
The development of this research will lead to results that could be transferred and applied in the clinical field of human oncology. In fact, identifying novel molecular pathways involved in CRC and understanding the molecular machinery that controls key events of tumorigenesis might allow devising reagents that target specific component, to achieve more efficient and selective killing of malignant cells.