Instytut Biologii Medycznej PAN

MAESTRO-Summary


MAESTRO: 2011/02/A/NZ3/00068

In 2008, when our project was founded, an estimated 1.2 million new cases of colorectal cancer were diagnosed worldwide and this number was even higher in 2018 (1.8 million). It is the third most common cancer in the world but the second in Poland. The survival rate of cancer patients declines rapidly if the cancer cells undergo spreading through vasculature to distant places in an activity called metastasis. The processes leading to the tumour metastasis are still not clear. Scientific findings provide evidence that distant microenvironment is primed and ready prior to the arrival of cancer cells, thereby creating a “landing dock” for future metastatic growth.
The goal of our project was to identify the possible cancer-derived agents that change the colon cancer cells and make them moving to distant organs. Identification of such agents may provide new targets for the anti-cancer strategies, which will be based on the inhibition of the factors that promote spreading.
The studies planned in this proposal focused on the way of how the factor that regulates the genes in the cell, called “Snail”, affects the places distant from the primary tumours that are targets for new tumour growth. Such places are called “pre-metastatic niche”. The existence of the pre-metastatic niche implies that metastasis to a particular organ is not a random occurrence, but rather a predetermined event. Finding the specific factors involved in pre-metastatic niche formation will help to develop future strategies to block metastasis.
In the first stage of our work, by creating colon cancer cells that contain more than usual amount of the Snail factor, we confirmed that Snail changes the colon cancer cells to make them more mobile and more invasive – ready to pass through the vasculature wall. Using a novel methods of global comparison of normal cancer cell and cell with high amount of Snail we identified several components that are either increased or decreased in the colon cancer cells with increased levels of Snail factor. This result lead us to find a new, previously undetected in colon cancer cells factor called Neuromedin U that level is increased when the cells become more mobile. We have also established the effect of Snail on the presence of gene-regulating molecules called miRNA that affect the invasiveness of cells with high levels of Snail. These findings may help in diagnosis if the patient’s cancer cells are on the stage that will make them to move to distant places as well in prognosis of the formation of new metastatic tumours. We have also described several processes that are targeted by Snail and lead to the increased mobility of the cells. Further we isolated a small fragments of the cancer cells that transport various cancer factors into normal cells that will help that way in formation of the above mentioned pre-metastatic niche to facilitate the new tumour growth.
We have also performed several experiments showing the role of Snail in spreading of cancer cells in animal models in vivo. We have shown that small fragments of colon cancer cells, especially from cells with high levels of Snail, traveling through vascular system increase the presence of inflammation focuses in the lungs of mice with tumours.
We believe that our work performed in course of this project will help to develop the strategies to better diagnose the presence of cancer cells moving through the patient’s vasculature as well as to plan a future strategies to block that movements and spread of the tumour.