RAB5, master regulator of tumour, mesenchymal invasive programmes

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Published: 20 Nov 2012
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Dr Giorgio Scita – IFOM University of Milan, Italy

Dr Giorgio Scita talks to ecancer about the trafficking of cell membranes and the plasma membrane receptor and the reasons why previous attempts to understand metastasis have been unsuccessful. New developments in research show that due to tumour cell's flexibility to use different vessels to spread, stopping one pathway can stimulate a different type of metastasis.

The approach we are taking is an approach that has stemmed from a number of recent observations that revealed that one process that was unexpected to be involved in cancer dissemination which is trafficking of membrane and plasma membrane receptor trafficking which originally was thought to be a way of downregulating signal. It turns out to be a way of conferring a special dimension and polarity to a cell, in particular to a cancer cell.

The other point that is very relevant, the last ten years, 10-15 years, it has become clear that probably one of the reasons that we have been extremely unsuccessful in combating metastasis is because tumours utilise a very plastic mode of disseminating. What I mean is that tumour cells are very flexible so they can use the bicycle, they can use the car, they can use… they can go walking and any of these means are utilised by tumours in order to spread into the surrounding tissues. So, for instance, one attempt to block one of these pathways, metalloprotease inhibitors which are proteolytic enzymes that allow to generate space into the surrounding tissues has been a total failure in clinic probably also because these treatments stimulate a different mode of dissemination. So instead of taking the bike they will take a car but they will still go from point A to point B.

What is the system for this?

Primarily using… so we have originally started from a cell biological type of approach, so basic fundamental cell biology, and we are moving more and more towards models of tumour metastasisation that includes xenografting relevant cancer cell lines in order to understand whether those cancer cell lines injected into a mouse model will be able to metastasise into the surrounding tissue. We go and we knock specific endocytic genes in order to assess the impact on migration and dissemination of this cancer cell line injected into mice.

Then the other approach, we go to clinic, to the clinical sample, human patient. Based on the information that we have got on endocytic molecules affecting migration, we look to see whether those molecules are dysregulated in cancer. So one of the works that I’m going to be presenting pertains to one of these molecules which is called, it doesn’t really matter, RAB5, whose expression is upregulating breast tumours. In particular in those patients that are node negative, so lymph node negative, ER positive, predicts breast cancer, predicts for survival. So the upregulated levels are associated with poor survival and as you are very well aware, the node positive, ER positive cancers are the ones that generally perform very well but are generally also the ones for which it’s very difficult to predict the outcome, the disease outcome.

We are exactly trying to mimic, at least as much as we can, the process of tumour development in the mammary fat bed of the mouse which is the site of injection. In particular we utilise a new technique, relatively new, which is two photon microscopy which affords to image cancer cells deep into the tissues and by that we can really literally monitor the first step of tumour metastasisation which is the detachment of single individual cells from the tumour mass on their way to enter the blood stream or the lymphatic. So this technique allows us to really watch this very initial step of motility and, of course, the goal would be to try to curb this mode of motility in order to help prevent this dissemination. It’s clear that one drug will not do it and it’s going to be multiple drugs probably affecting all these different modes of motility that eventually might be successful in curbing, at least, tumour dissemination.