Tuesday, March 16, 2010

Cancer and Cellular Connections

Days of strange co-incidences. Today a friend in the USA sent me a fascinating little article from the Howard Hughes Medical Institute. Basically the story goes like this:

Cancer cells have very strong "pulling power", they tightly bind together. This has serious therapeutic implications which be latter addressed. What struck me as so odd about this research was just yesterday I read how immune cells also rely on pulling power to ensnare and devour dangerous cells.
The research from Howard Huges Medical Institute is a wonderful example of modeling cell behavior. The stronger the cells bound together, the more aggressive the tumour. A recent research piece, excellently reviewed in this Scientific Blogging link, finds that Natural Killer cells rely on nanotubes which extent out and bind the target cell. The ability of NK cells to do this is very important because it plays a fundamental role in killing the target cell. Typically we think of cell mediated apoptosis(programmed cell death) to be mediated by specific molecules that binds to receptors in the target cell and initiate programmed cell death. That is obviously still important but the immune responses are not so neat and tidy, in fact it is more the case of a barrage of attacks against potential invaders to increase the probability of a major strike against the foe. This binding phenomenon touches on this in the following ways:

  • If an NK cell can obtain greater cell surface to cell surface contact with the target cell, it can release death initiating molecules that will be much more likely to find their target receptors(thereby overcoming a major probability problem for me regarding ligand-target receptor dynamics).

  • NK cells will also release oxidising agents, this is a major feature of the immune response. Again, the closer the cell, the more likely these agents will penetrate the cell wall of the target cell.  

  • The binding will effectively smother the target cell, thereby depriving it of nutrients, oxygen, and waste elimination. This will weaken the cell enhancing the possibility of programme cell death being mediated by a process that happens within the cell and does not require an external receptor mediated death signal. 

But wait, there's more ...

  • The tight binding of cancer cells may provide some insight into why angiogenesis is such an important issue for tumour progression. Many of the leading chemotherapeutic drugs are aimed at inhibiting angiogenesis. While this is a desirable goal it also carries many risks but hey die from cancer or take your chances what are you going to do? With such tight binding the cells would require extensive angiogenesis to maintain nutrients and waste elimination. 
  • It is often said that the immune responses do "recognise" tumour cells but fail to act. For as yet unclear reasons tumour cells are often resistant to immunological assault, though there is the possibility that for some as yet unknown reason tumour cells attract regulatory T cells, a line of T cells that serve to inhibit the immune response. I doubt that and in light of these two research pieces I am inclined to the view that tumour cells survive because the NK cells, which play a major role in cancer killing, cannot obtain a sufficient grasp of the tumour cell so as to maximise their cell consuming efficacy. 
  • It is well known that a detached cell is a cell in danger. As a detached cell will express various cytoskeletal proteins on its surface, and these proteins can initiate an immune response, such a cell will become a target for the immune system. This would not apply to cells that are typically not attached to other cells(blood cells, immune cells) because they would not be expressing the cytoskeletal proteins that are used to bind cells together. 
  • The tight binding of tumour cells serves not only to prevent cell detachment and so enhance cell survival, but also reduces the target area for molecule to killer receptor linkage. In fact the tighter binding has the potential to reduce cell exposure to potential immunological attack to a very great degree. 

Therapeutic Implications:

The reason why so many immunotherapeutic approaches may be failing is simply because solid tumours are more like a disciplined squad of rebels hell bent on holding their ground. Inducing cytoskeletal disruption may be an important pre-requisite for both immunotherapeutic and chemotherapeutic approaches to tumour treatment. There are agents known to attack these binding proteins. Colchicine, used to treat gout, is known to dissolve microtubules but also damages many cells.

There is a way around the above dilemma. I read this months ago and there is active research in the area. It involves a beautiful little idea of taking bacterial cells, cleaning out the insides, and then filling up the same with some toxic material. This "mini-cell" will then bind to a tumour cell, and release it contents. Because bacterial cell walls typically contain proteins that mount a strong immune response, these mini-cells confer a dual advantage in targeted chemotherapy and enhanced immunological response. For more information about bacterial wall proteins, have a look at(Warning - difficult to read link because it is very technical)  PAMPS - Pathogen Associated Molecular Patterns.

To a man with a hammer everything looks like a nail. We always focus on that which we can place within some theoretical framework. Biology is very much about chemistry but as these articles demonstrate simple high school physics can also be very important.

Finally ... 

For those so interested I highly recommend the Scientific Blogging article on the NK cell use of nanotubes. The research on which that item is published by PNAS.