Would it surprise you to learn that we share half of our DNA with a banana? Our DNA sequence codes for our individual uniqueness and yet there are few, if any, similarities to draw between humans and bananas. In fact we only differ from our closest ancestors, the chimps, by 1% at the DNA level. So what makes us human beings the complicated creatures that we undeniably are?
It turns out that a very small amount of DNA can code for a much larger spectrum of proteins, the functional units in our bodies, and it is this process that provides our complexity as a species. One way this variation is achieved is through 'alternative splicing'.
Alternative splicing refers to the cutting up and sticking back together of a gene before the final protein is formed. This occurs naturally for many genes and allows for the functional parts of the protein to be shuffled around - sometimes resulting in proteins with very different or even opposing functions. For example, the protein Bcl-x(L) prevents a cell from dying, whereas its alternatively spliced variant Bcl-x(s) actually promotes cell death.
The balance of these variants is strictly controlled during development to allow cells and tissues to grow and function appropriately. However cancer cells are very unbalanced in this respect, favouring protein variants that help them to grow, survive and increase their blood supply. Unsurprisingly then, cancer cells prefer the pro-survival Bcl-x(L) over its sister variant.
This shows how clever cancer cells can be; rather than generating entirely new proteins they simply use alternative splicing to rearrange the ones that are already being made.
Luckily for us these changes in splicing can become drug targets, or become a means of diagnosing or monitoring of cancer. For example, differences in the splice variant repertoire of CD44, a protein involved in the survival and movement of cells, have been seen between metastatic and non-metastatic pancreatic cancer cells. When tumour cells become metastatic, i.e., spread from the initial tumour to other parts of the body, the patient’s likelihood of survival is reduced, so being able to monitor when this is expected to occur is very important.
However it would be much easier if there were protein splice variants that were unique only to tumour cells, avoiding the risk of targeting proteins that are needed by normal tissues. Fortunately this may indeed be the case. Cancer cells can actually activate entirely new splicing events within some genes, thus generating tumour-specific splice variants of certain proteins.
This has been shown most recently in breast cancer. The study used an advanced technique that allowed all the alternatively spliced variants in a cell to be examined in very high detail and compared for the first time between normal and cancerous cells. Multiple new variants were discovered that were unique to the breast cancer cells. The function of these new proteins, and their role in cancer, need determining on a case-by-case basis. However they may one day offer the elusive opportunity to exclusively target cancer cells with minimal side effects on the normal neighbouring tissue.
Navaglia F, Fogar P, Greco E, et al. CD44v10: an antimetastatic membrane glycoprotein for pancreatic cancer. Int J Biol Markers 18:130–8 (2003).
Eswaran J, Horvath A, Godbole S, Reddy SD, Mudvari P, Ohshiro K, Cyanam D, Nair S, Fuqua SA, Polyak K, Florea LD, Kumar R. RNA sequencing of cancer reveals novel splicing alterations. Scientific Reports 3:1689 (2013).