A Role for Alpha-2-Macroglobulin in the Cancer Immunity of Naked Mole-Rats

Naked mole-rats are near immune to cancer, in addition to living far longer and with far less of a functional decline over the course of a lifetime than is the case for other, similarly sized rodent species. Research into this cancer resistance has so far led to evidence for greater efficiency in cancer suppression genes, particularly with regard to being triggered by cell crowding of the sort that takes place in tumors, and higher prevalence of high molecular weight hyaluronan in naked mole-rat tissues. These are unlikely to be the only factors involved.

Here researchers outline a role for alpha-2-macroglobulin (A2M) in cancer suppression; it appears to inhibit tumor growth in multiple mammalian species through a variety of mechanisms that are as yet not all that well characterized. Naked mole-rats are found to have a very high level of A2M in their tissues, which may be an important component of their resilience to cancer. Older humans exhibit lower levels of A2M than their younger counterparts, which may be one of the numerous contributions to age-related vulnerability to cancer. Unfortunately, A2M interacts with a sizable number of other proteins, which will no doubt ensure that confirmation of its mode of action will require significant further time and investment. Even absent that confirmation, however, there is now evidence of significant tumor suppression in mice through delivery of A2M. That seems quite promising.

The naked mole-rat (NMR), a subterranean rodent, tolerates hypoxia, hypercapnia, avoids many physiological characteristics associated with aging and, most importantly, exhibits pronounced resistance to cancer. Transcriptome analysis of NMR liver compared to wild-derived mice revealed very high expression of cell adhesion molecules involved in tumour development as well as the pan-proteinase inhibitor alpha2-macroglobulin (A2M).

Earlier, we have shown that the level of A2M in human blood decreases with age and exposition of tumour cells with activated A2M (A2M*) inhibited many malignancy-associated properties of tumour cells in vitro by inhibition of members of the WNT/ß-catenin pathway. Therefore, we hypothesized that the reduction of A2M in aged humans may facilitate tumour development. A2M is capable of binding to most proteinases and many growth factors, hormones, and cytokines. Binding to its receptor, the low density lipoprotein receptor-related protein 1 (LRP1, also known as CD91), mediates fast clearance of tethered peptides and proteins. A specific role of A2M in cancer cell metabolism and development has not been elaborated in detail yet.

Here we show that A2M* modulates tumour cell adhesion, migration, and growth by inhibition of central signalling pathways such as phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and SMAD. A2M* up-regulates the tumour suppressor PTEN, CD29, and CD44 but does not evoke epithelial-mesenchymal-transition (EMT). Furthermore, A2M* was found to down-regulate microRNA-21 (miR-21), which is a dominant inhibitor of PTEN expression.

Notably, A2M* inhibits growth of tumours in nude mice independent of their origin, and induces tumour necrosis in tumour tissue and tumour slices cultures. Transcriptome analysis displayed fundamental and unexpected insights in regulatory power of this ancient and highly conserved human plasma protein. The unique features of using A2M* as a novel anti-tumorigenic therapeutic in cancer patients prompted us to perform this study: increasing the fraction of activated A2M* in humans might represent a novel approach for cancer prophylaxis and treatment.

Link: https://doi.org/10.1371/journal.pone.0189514


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