1) Oncogene-driven thyroid cells transformation: normal versus cancer stem cells

Stem cells have the ability to preserve themselves through self-renewal as well as the capacity to generate differentiated cells. Being that cancer is considered an unregulated and self-renewing disease, understanding the molecular events controlling this process is fundamental for the identification of those mechanisms that underlie cancer cell proliferation. Although it was postulated that tumors may often originate from stem cell transformation, the target cell of transforming mutations, is still unknown. Nonetheless, stem cells are still the sub population with a high probability of transformation for two reasons: i) susceptibility of already activated self-renewal machinery in gaining a further aberrant activation; ii) opportunity of accumulating mutations in individual stem cells that persist for longer periods of time when compared to most other mature cell types. Therefore, this project proposes to identify the genetic changes which occur in stem cells that leads to their transformation  into cancer stem cells (CSCs). We will evaluate the capability of transformed stem cells to strictly regulate self-renewal and create a xenograft tumor, which morphologically and genomically resembles the original patient’s tumor and exhibits individual heterogeneity. The self-renewal mechanism could be even more pronounced in CSCs that have been shown to be particularly clonogenic. Recent evidence hints at the possibility that many pathways, classically associated with cancer, may also regulate normal stem cell development.

2) Cancer Stem Cells: new molecular targets involved in colon cancer metastasis

The insurgence of metastasis accounts for 90% of deaths in patients with colon cancer. Tumor cells responsible for metastasis usually survive in a hostile environment and face potentially lethal conditions. This is a result from the sophisticated mechanisms that regulate homeostasis in humans. In particular, cells able to cause metastases must have an increased proliferating capability, a marked resistance to “harsh” environments (probably correlated with increased niche plasticity), a decreased tendency to apoptosis as well as altered adhesion and mobility properties. All these characteristics are present  in tumor stem cells that represent the cell population most likely responsible for metastasis formation. Investigating the processes that lead to metastases and developing strategies able to prevent their formation, are major objectives in oncology.

Although it is clear that larger and more invasive tumors represent a more efficient source of metastatic cells, the cell population able to migrate from the primary site and generate distant metastasis, remains largely unknown. We recently showed that colorectal cancer contains a small variable number of cells that express CD44v6. The latter are uniquely able to generate metastatic tumors in orthotopic xenograft models,

whereas cells lacking CD44v6 can be tumorigenic, but are unable to produce metastasis or serial xenografting. While MET is widely expressed in CRC cells, CD44v6 is absent but can be induced by HGF, OPN or SDF-1, which are able to turn undifferentiated non-metastatic cells into metastatic ones. The main role played by CD44v6 in CRC spreading was confirmed by analysing two large cohorts of patient tumors. This demonstrated that high expression of CD44v6 is an independent negative prognostic factor in patient survival. Moreover, the targeting of either CD44v6 or MET, prevents migration and neutralizes the metastatic potential of tumorigenic CRC cells and therefore  the control of tumor spreading.

Topics ultima modifica: 2015-10-12T11:52:42+00:00 da admin