Projects / Programmes
Involvement of the Lysosomal Cysteine Peptidase Inhibitors in Progression and Metastasis of Mammary Cancer
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| B200 |
Biomedical sciences |
Cytology, oncology, cancerology |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
Cancer, cysteine cathepsins, inhibitors, cancer treatment, tumour microenvironment, metastasis, breast cancer
Researchers (10)
Organisations (2)
Abstract
Metastasis is the most serious challenge for cancer treatment, representing the major death-determinant and causing a significant reduction in the quality of life. A hallmark of the malignant process is the acquisition of an invasive phenotype that allows neoplastic cells to invade surrounding tissue and disseminate into specific organs. The objectives of the present project are to identify molecular pathways involved in the regulation of interplay between cancer cells and their microenvironment both at primary and secondary sites.
Proteases are now recognized as key regulators of a complex network of interacting molecules that modulate the properties of cancer cells and their microenvironment. Among them are lysosomal cysteine peptidases (clan CA, family C1), so called cathepsins, involved in a number of cellular processes important for normal cell function as well as playing an important role in some pathological conditions, such as cancer. The expression of cysteine cathepsins have often been positively correlated with a poor prognosis for cancer patients and measured as potential prognostic markers for several types of cancer. Proteolytic activity of cysteine cathepsins is regulated by endogenous inhibitors stefins, cystatins and serpins. The fluctuations in their expression have been linked to pathological states including cancer; however, their specific roles in that process remain poorly defined.
This project was initiated to critically evaluate the importance of the extracellular and intracellular lysosomal cysteine peptidase inhibitors from tumor cells and different cell types in the tumor-supporting stroma for tumor progression and metastasis. The work is based on genetically modified mice with a constitutive deficiency for protease inhibitors (stefin B and cystatin C). Transgenic mouse model of mammary carcinogenesis – Tg(MMTV-PyMT) – will be initially used for analyses of different stages of tumor progression (tumor growth, histopathological grading, etc.) and metastases (incidence, growth, etc.) in correlation to protease inhibitors expression. We will immunohistochemically analyze primary tumors and metastasis of PyMT mice for processes important for tumor development and progression, including angiogenesis, cell proliferation, apoptosis, invasion, etc. The primary tumor cells, obtained from mammary tumors of PyMT transgenic mice (wild type and depleted in protease inhibitors expression) will be used as a basis for investigations of tumor-stroma cells interactions, pre-metastatic niche concept, in vitro invasion and other assays. In order to dissociate the effects of primary tumor cells and tumor microenvironment for tumor invasion and metastasis, we will use an adoptive transfer models, either implanting tumor cells in the fat pad or injecting them in the tail vein of recipient mice.
The use of genetically modified animals is essential to study the early steps of cancer progression and metastatic dissemination in a complete organism with an adequate associated environment. However, the current project aims at reducing the need for animal use through the development of alternative in vitro methods. Transgenic (MMTV-PyMT) mice cells will be obtained through the consortia of the EU FP7-HEALTH project “Understanding and fighting metastasis by modulating the tumour microenvironment through interference with the protease network.” (MICROENVIMET), FP7-HEALTH-2007-A / 201279 (O. Vasiljeva co-PI), 2008-2012.
Proteases are currently one of the major targets for new therapeutics. Moreover, protease inhibitors as well as the use of apoptosis-based strategies are currently of major relevance in cancer treatment. Therefore, the results of the proposed project will be of great importance in evaluation of cysteine cathepsins as possible therapeutic targets in cancer.
Significance for science
This project is of high biomedical relevance for the field of oncology. Proteases are currently one of the major targets for new therapeutics (Turk 2006, Nature Reviews Drug Discovery). Notably, lysosomal proteases have already been validated as relevant targets for cancer treatment, whereas several compounds targeting lysosomes and/or lysosomal proteases are already in preclinical or clinical testing. Moreover, the project is expected to open new avenues in the areas where the exact roles of cathepsins inhibitors and their signaling pathways were unknown, largely unclear or controversial. The gained knowledge will thus not only significantly contribute to our understanding of the complex biological phenomena, but will also be instrumental in biomedical research to understand and develop novel strategies to combat cancer and other hyperproliferative diseases based on modulation of the activities of lysosomal proteases.
Significance for the country
Although the proposed research is basic research, it also has its applied component and can be classified as strategic basic research. As can be seen, members of the group as well as project partner Prof. Dr. J. Kos (Faculty of Pharmacy) have extensively collaborated with Slovene industry (Lek, Krka). The work also offers great opportunity for students to be trained in the most advanced methods and areas, such as proteomics, which is currently being established at the IJS within the group, cancer genomics together with European and other international partners, and trials of novel potent treatment compounds. All these fields have namely high international priority as they are of extreme importance drug development. In addition, members of the project team have received wide-spread international recognition which is very important for the world-wide promotion of Slovenia and as such also for preservation of national identity of Slovenia.
Most important scientific results
Annual report
2012,
2013,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2011,
2012,
2013,
final report,
complete report on dLib.si
