In a recent study published in the journal Proceedings of the National Academy of the Sciences, the research group of Professor Michael Hall from the University of Basel has shed light on the role of mTORC1 signaling in blood, and the relevance role it has for the physiology of, in this case, human liver cancers [1].

mtor_liver

Pictured: Human liver tumor with active mTORC1 signaling (top) correlates with increase of FGF21 stress hormones (below). Image Credit: University of Basel, Biozentrum

Research shows us that deregulation of mTOR signaling raises the chances of developing serious metabolic illnesses, including obesity, diabetes and cancer.

That's because the protein mTOR plays a central role in modulating metabolism and cell growth, as well as the downstream signaling of over 800 proteins. It can also be said then that mTOR functioning can play an important part in the evolution of individual disease.

Inside the cell, this regulatory protein is found as two functionally different structures, protein complexes called mTORC2 and mTORC1.

Body Physiology controlled by mTORC1 in liver

In animals, the liver is a vital organ that controls the physiology of the body in a way that listens and responds to nutrient absorption during digestion. Hall's group investigated the underlying molecular mechanism of mTORC1's nutrient detector. What their work revealed is that the presence of mTORC1 in the liver decreases not only the locomotor activity and body temperature of the mice being studied, but, and perhaps more importantly; it decreases the metabolism of fat lipids.

The researchers also found that when the mTORC1 signaling was amplified, which is one sign associated with liver cancer, it boosted levels of the stress hormone FGF21. This, however, also has the side effect of depleting the amino acid glutamine from the body. Supplementing glutamine into the diets of the mice reduced the levels of the FGF21 stress hormone, effectively avoiding the physiological damages suffered from prolonged exposure.

Treating Liver Cancer with mTORC1 Inhibitors

According to research, many cancers have a particular affinity for glutamine. This particular bit of research suggests that irregular signaling of mTORC1 leads to increased production of stress hormones, perhaps as a physiological coping mechanism.

The lead author of the study cell biologist Dr. Marion Cornu, comments, We were excited to see that in human liver tumors mTORC1 signaling correlates with FGF21 expression.

And it is very exciting. These findings by Hall's team supplies direct evidence that cancer therapies for glutamine-hooked malignancies can be treated using mTOR inhibitors, including, Rapamycin and Dasatanib.

It also provides a favorable outlook toward the development of new therapies that can effectively avoid deregulating vital organ function while still blocking the tumor growth.

Medications used to inhibit the mTOR pathway are also routinely employed to control the immune reaction in patients receiving organ transplants. Interestingly, it's not uncommon for these patients to develop bone problems.

New research, funded in part by the University of Washgnton, seeks to further our understanding about the ways these medications work and how they open pathways that create optimal conditions for the patient's recovery.

Fanxin Long, a professor of medicine and developmental biology, and also one of the contributers to the research said, It's still early, but our finding seems to point out that activating the mTOR pathway may be a good way to stimulate bone growth."

This particular research paper, titled, Foxp3 T cells inhibit anti-tumor immune memory modulated by mTOR inhibition, found that blending a CD4 antibody with an mTOR inhibitor expels solid tumors from the body and may help to sharpen the memory of the immune system. [2]

"Many develop bone problems within a few months of receiving transplants because of the heavy doses of immunosuppressors they receive," explained Long. "Scientists have not looked carefully at how drugs used to prevent organ rejection can have a detrimental effect on bone, but our study would suggest that if those drugs inhibit mTOR, they could disrupt bone formation."

This is a new twist because much of the current focus in mTOR-related drug development has been on compounds that inhibit the pathway to shut down cancer cells."

Further research is needed which can look deeper into the WNT proteins which advise bone cells to activate mTOR so as to stimulate bone growth. For his next research project, Long is aiming to discover exactly what happens further down the path to produce fresh bone. If the precise targets can be identified in the bone development process, new medicines could potentially come online without creating undesired side effects in people who have osteoporosis.

The same could be said for medications that targeting mTOR signaling in the liver without impairing vital organ physiology.

Sources

M. Cornu, W. Oppliger, V. Albert, A. M. Robitaille, F. Trapani, L. Quagliata, T. Fuhrer, U. Sauer, L. Terracciano, M. N. Hall. Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21.Proceedings of the National Academy of Sciences, 2014; DOI: 10.1073/pnas.1412047111 

Jianquan Chen, Xiaolin Tu, Emel Esen, Kyu Sang Joeng, Congxin Lin, Jeffrey M. Arbeit, Markus A. Rüegg, Michael N. Hall, Liang Ma, Fanxin Long. WNT7B Promotes Bone Formation in part through mTORC1. PLoS Genetics, 2014; 10 (1): e1004145 DOI: 10.1371/journal.pgen.1004145

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