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T-cadherin: a functional determinant and early prognostic marker for malignant transformation of squamous cell carcinoma
| Third-party funded project |
| Project title |
T-cadherin: a functional determinant and early prognostic marker for malignant transformation of squamous cell carcinoma |
| Principal Investigator(s) |
Resink, Thérèse J.
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| Co-Investigator(s) |
Erne, Paul
Büchner, Stanislaw
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| Organisation / Research unit |
Departement Biomedizin / Signal Transduction (Resink/Erne) |
| Project start |
01.02.2010 |
| Probable end |
31.01.2013 |
| Status |
Completed |
| Abstract |
Background: Skin cancers are becoming an increasingly important public health problem worldwide. Cutaneous squamous cell carcinoma (SCC) is the second most common cancer of the skin and its incidence is estimated to double within 20 years. SCC are diverse in subtype with clinical behaviors, ranging from indolent to aggressive tumors with significant metastatic potential. While the case-fatality rate for SCC is only ~1%, overall mortality arising from metastatic SCC exceeds that of melanoma, which is far more lethal but less common. Early identification of SCC lesions with potential aggressive invasion and malignant behavior and understanding of molecular events participating in initiation and/or progression of these lesions will help the design of novel strategies to prevent and/or treat these cancers. Inappropriate expression or function of cadherins underlies many diseases of the epidermis. Alterations in expression of keratinocyte adherens junction cadherins, E- and P-cadherin, are recognized to participate in SCC progression. Expression of T-cadherin (T-cad) on keratinocytes was identified only in 2002, and its role in keratinocyte (patho)biology remains remarkably unexplored. Our recent immunohistochemical studies revealed distinct variations in expression levels and localization of T-cad within different zones of SCC that suggest important functions for T-cad in keratinocyte differentiation, tumor demarcation, directional invasion, progression and tumor angiogenesis. Our preliminary experiments using normal keratinocyte and SCC cell lines indicate striking effects of T-cad on cell phenotype and, proliferation and motility/invasion. Therefore, T-cad likely plays a major role in the (patho)biology of keratinocytes and loss of T-cad expression may be an important determinant in acquisition of aggressive invasive behavior.
Aim: To investigate the role of T-cad in the progression and malignant transformation of SCC.
Experimental approaches:
1. Immunohistochemical analyses of skin specimens from patients with SCC to examine the involvement of T-cad in the growth and differentiation switch of keratinocytes. T-cad expression patterns will be examined in conjunction with E-, P-cadherins and markers specific for proliferation, growth arrest, apoptosis, survival or differentiation.
2. Retrospective immunohistochemical investigation of patients with primary cutaneous SCC who developed metastasis to lymph nodes to determine whether or not loss of T-cad expression in primary cutaneous invasive SCC correlates with lymphatic invasion, lymph node metastasis and patient outcome independent of other tumor features.
3. Examination of T-cad-specific functions relevant to epidermal integrity and tumor progression in 2D-monolayer and 3D-spheroid cultures of normal human keratinocyte (HaCaT) and human epidermal SCC (A431) cell lines stably transduced with respect to overexpression or deficiency of T-cad. Functions include proliferation, migration, invasion, survival/apoptosis. Alterations in cell morphology and cytoskeletal organization will also be examined.
4. Investigations aimed at delineating signal transduction pathways that mediate T-cad-dependent effects on HaCaT and SCC behaviour.
5. Use of endothelial cell and SCC cocultures in 2D and 3D to examine whether T-cad expression on SCC influences tumor angiogenesis or tumor cell intravasation.
6. Exploitation of the chick embryo chorioallantoic membrane assay and a murine xenograft model to investigate whether modulation of T-cad expression on SCC alters their tumorigenic, invasive, angiogenic or metastatic potential in vivo.
Significance: This study will generate completely novel in vitro and in vivo information on the function of T-cad in keratinocyte biology and pathobiology, and will expand knowledge on cadherin-based mechanisms that control the growth and differentiation switch of keratinocytes. |
| Financed by |
Foundations and Associations
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12/05/2024
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