Naked Mole Rat Tumor Resistance: The CD44 and High Molecular Weight Hyaluronan Connection

I wrote this blurb a few months back. Naked mole rats are highly resistant to cancer. No one knows why, here I offer a hypothesis (which sounds reasonable to me).

Recent research has revealed that naked mole rats are resistant to cancer and one of the major factors that could promote this resistance is the unusually long hyaluronan (HA) polymers found in their extracellular matrix. The article mentions that the tough, stretchy matrix which clogs drains could restrict cell growth and probably tumor metastasis as well.

 

http://www.scientificamerican.com/article.cfm?id=simple-molecule-surrounding-cells-in-mole-rates-prevents-them-from-getting-cancer

 

However there could be more to this phenomenon than tough cell matrices. In my lab, we work with proteins like CD44 which are involved in HA signaling. HA is a very important ligand for CD44 and it is how CD44 exerts some of it’s critical signaling functions in the cell. CD44 is present in many tumor cells and there are many variants of CD44, however what is most fascinating about this receptor protein is that it has dual functions. It can either promote tumor growth and metastasis or it can act as a tumor suppressor. And what determines the fate of CD44 function? Well as extensive research has demonstrated, CD44 function is dependent on the size of the HA ligand it interacts with. This quote is taken directly from Jeanne M.V. Louderbough et al. (2011):

 

 “Hyaluronan influences intracellular signaling by binding to cell-surface receptors, namely CD44 and RHAMM, but it also has context- and size-specific biological activities (39). For example, high molecular weight (HMW) hyaluronan has been shown to inhibit tumorigenesis by promoting cell-cycle arrest under conditions of high cell density, to inhibit CD44-mediated cell invasion in breast cancer cell lines, and to be antiangiogenic and antiinflammatory (26, 43�"47). In contrast, low molecular weight (LMW) hyaluronan oligomers can promote cell motility, CD44 cleavage, and angiogenesis (33, 48, 49). Thus, hyaluronan-mediated biological functions are strongly size dependent.”

 

Previous research has shown that high molecular weight hyaluronan acts as to inhibit tumorigenesis via CD44-mediated pathways, while low molecular weight hyaluronan promotes tumorigenesis through CD44 mediated pathways. For more detail of the relevant mechanisms involved here is a link to the appropriate figure in the article:

 

http://mcr.aacrjournals.org/content/9/12/1573/F2.expansion.html

 

Using this evidence it is easy to make a connection between the naked mole rat’s tumor resistant phenotype and the high molecular weight HA present in the animal’s cell matrix. This phenomenon could offer a mechanism or at least one out of many mechanisms that can explain why naked mole rats are tumor resistant.

 

The reality of the situation is that biology and biochemistry, especially cancer biology is very complicated and there are probably many factors involved. And the studies present in this review article are mostly related to breast cancer, this is the evidence we have from breast cancer cells. However the function of CD44 and HA is implicated in many other tumors, not just breast cancer cells. But the best we can do is start with a simple hypothesis and simple propositions. The evidence here implies a reasonable hypothesis that in naked mole rats, tumor resistance is somehow related to HA signaling. The size of HA fragments found in the extracellular matrix could make all the difference between normal, healthy cells and malignant tumors.

 

 

Reference:

 

Jeanne M.V. Louderbough et al. Understanding the Dual Nature of CD44 in Breast Cancer Progression; Molecular Cancer Research 2011; 9

Author's Note

Read it like a Jazz poem.