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EGFR (epidermal growth factor receptor) has been intensively studied in cancer and treatments have been developed to inhibit EGFR signaling. Sialylation of EGFR is known to block dimerization and down regulate signaling. I just read this paper:

Liu et al. 2011. Sialylation and fucosylation of epidermal growth factor receptor suppress its dimerization and activation in lung cancer cells. PNAS 108: 11332–11337. (basically just read conclusion if you don't have time).

What I don't understand is that the authors seem to say that increasing sialylation might be a good thing to prevent cancer progression since it inhibits EGFR dimerization. However, wouldn't this go against almost 50 or 60 years of research that suggest that increased levels of sialic acid are one of the well known hallmarks of cancer that aid in its progression and metastasis? What could explain this apparent discrepancy?

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1 Answer 1

Wikipedia claims (without reference) that

Metastatic cancer cells often express a high density of sialic acid-rich glycoproteins. This overexpression of sialic acid on surfaces creates a negative charge on cell membranes. This creates repulsion between cells (cell opposition)[5] and helps these late-stage cancer cells enter the blood stream.

so I assume this is a summary of the "50 or 60 years of cancer research" that you mentioned. I don't doubt you, I've just never read up on this particular aspect of cancer. Be that as it may, there is a difference between a cell's expressing high levels of sialoglycoproteins overall, and inducing high sialylation of one protein in particular, in this case EGFR.

As you may be aware, EGFR dimerization induced by multiple methods, including EGF binding, overexpression, mutation, chemical or antibody crosslinking, etc. activates tyrosine kinase domains in its intracellular region to auto-phosphorylate specific Tyr residues in its tail, which then recruit adapter and scaffolding proteins which support downstream signal transduction.

The paper you read shows how increasing sialylation of EGFR reduces its trans-affinity for itself and inhibits dimerization, and hence the downstream signaling cascade. This is a good thing in certain types of cancer which are driven by aberrant EGFR signaling, whether through overexpression of EGF and/or EGFR, mutations in the kinase domains, mutations in the dimerization domains, or otherwise.

This paper is also a great example of an apparent bad thing turning out to be good, when properly targeted and controlled. Excess sialylation of a cell may be bad, but specific over-sialylation of EGFR could turn out to be very useful, if we can learn how to modulate and target it. Another common example of this phenomenon is radiation therapy. Normally, high levels of radiation are bad for your body, and can actually cause cancer, among a range of other illnesses. But, there are many different ways of specifically targeting radiation to a tumor to kill it while sparing (to varying degrees) the surrounding tissue and the rest of the body.

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Thanks for the response Matt. I guess I just don't see how it is possible to target siaylation of a specific glycoprotein in a cancer cell. Not only would that likely require cancer cell specificity, it would require activation of some metabolic pathway that would only sialylate EGFR--in otherwords subcellular accuracy. I don't think I've ever read of a way to specifically control glycosylation of a targeted single protein. I guess I simply don't agree with the authors' conclusions where they state that shutting down transferases might be a "bad" thing because it would promote EGFR dimers. –  GPI Apr 2 '13 at 20:15
    
I know many people have long been trying to create glyco-transferase inhibitors to try to inhibit things like sialyation of cancer cell surfaces to prevent metastasis. This paper alludes to the idea that this might be bad because it would promote EGFR activation. I can't see why the authors would reach such a conclusion based solely off the study of just 1 glycoprotein when there are many others on the surface that may have negative influences if excess sialylated. –  GPI Apr 2 '13 at 20:20
    
@GPI - that's why I put "specific over-sialylation of EGFR could turn out to be very useful, if we can learn how to modulate and target it" in there. It's a pretty big if. –  MattDMo Apr 2 '13 at 20:38

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