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Identification and functional analysis of key genes in hormone-sensitive human epithelial tumors

Research project P5/31 (Research action P5)

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Description :

Human cancer is a complex disease that is characterized by its high prevalence and its highly dynamic nature. Through a multistep process reflecting multiple genetic alterations, cells progressively evolve from normality via a series of premalignant states and intermediate steps into highly invasive and malignant tumor cells. Although the primary genetic changes may differ substantially among different cancer types and even among different patients, cancer cells ultimately acquire common phenotypical characteristics that can be brought down to a small number of cellular, biochemical and molecular traits. These include changes in intracellular signaling leading to self-sufficiency in growth signals and evasion of apoptotic cell death, unlimited proliferative potential, changes in intermediary metabolism, sustained angiogenesis, and changes in cell adhesion, motility and invasive potential. One of the main challenges of contemporary cancer research is to map the individual genetic changes, to identify the key genes and the functions of the encoded proteins that link these changes to the typical cancer phenotype. Moreover, as many of the traits mentioned above appear to be interconnected, an ultimate understanding of the cancer phenotype requires integration of these changes and identification of potential functional networks in the cell and the organism.

In the proposed scientific network several established outstanding Belgian research teams and several young emerging teams are brought together in an attempt to look for such key genes and to identify such links. Each team has its own complementary expertise and international recognition in one of these individual traits and uses one of four common endocrine-regulated epithelial cancers, i.e. breast, prostate, cervical and thyroid cancer. The creation of a scientific network of partners creates a unique opportunity to study and compare the traits mentioned above and the underlying genes in multiple related cancer types, to build on the expertise of other partners to look for potential links between different traits and to share specific, highly sophisticated equipment and technologies.

The ultimate aim of the collaboration is to identify genes that are relevant to the malignant phenotype, and more particularly genes that can be used as novel diagnostic or prognostic markers and as potential therapeutic targets. Specifically, the partners of this proposal will attempt to answer the following questions:

1. What are the key genes responsible for disturbed cell signaling and cell cycle regulation in thyroid tumors with various degrees of malignancy? Can master genes be identified that are also relevant to tumors in other hormone-regulated target tissues?

2. What are the underlying mechanisms, and what is the impact of dysregulated expression of cell adhesion molecules and more particularly of the cadherin-catenin system on tumor cell signaling, cell interactions and motility?

3. Is there, between the four cancers selected, a common pattern of expression and activation of the various matrix proteases involved in cancer progression? Which are the regulatory mechanisms that control their expression in these malignancies?

4. Can we identify major changes in cytoskeletal proteins and in the proteins and phospholipids controlling their activity? Are these changes related to particular stages of tumor development?

5. Which are the molecular mechanisms that control angiogenesis in the four cancers investigated? What is the involvement of matrix proteases, and are angiogenesis inhibition strategies equally effective in these cancer types?

6. Which are the common molecular mechanisms that sustain the osteotropic properties of metastatic cancer cells in the cancers evaluated?

7. Is the increased lipogenesis observed in many breast and prostate cancers also a characteristic of the other cancers studied? Can it be related to a common set of disturbances in cell signaling? What is its value as a marker of poor prognosis and as a novel target for antineoplastic therapy?

8. Can specific transgenic Xenopus frogs be used efficiently in order to address several of the questions raised?

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