PI Eric Lagasse
Title The Role of mTOR (mammalian Target Of Rapamycin) Complex 1 and 2 in liver regeneration and ectopic liver organogenesis
Description Liver failure is a major cause of morbidity and mortality in the Western world. Although the liver is mitotically a quiescent organ in adult life, parenchymal regeneration can occur through the proliferation of the two major types of hepatic epithelial cells, hepatocytes and biliary epithelial cells. Akt and its downstream mTOR signal are likely to contribute to this process. Indeed, transient increase of activated forms of Akt, mTOR, TSC2, p70S6K1 and 4E-BP1 was correlated with the growth response following hepatotectomy in animal models. Accordingly, the mTOR inhibitor rapamycin was effective in retarding proliferation of hepatocytes in the same model of liver injury.
Recent findings indicate that mTOR is shared by two different complexes with specific funtions, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), and a careful revision of the literature suggests that the previous liver regeneration studies were limited to the analysis of only mTORC1 activity. The major difference between the two complexes is the substrate specificity factors, raptor in mTORC1 and rictor in mTORC2. Briefly, mTORC1 regulates mRNA translation and ribosome biogenesis while mTORC2 regulates actin cytoskeleton. Importantly, according to recent investigations, Akt, apart from being an upstream activator of mTORC1, is also a downstream effector of mTORC2, being this latter responsible for its full activation. Importantly, mTORC2-mediated Akt activation is emerging as a critical inducer of cell growth and motility.
In the mouse model of human tyrosinemia type I (the FAH-/- mouse) -a form of acute liver failure where spontaneous liver regeneration is impaired- intraperitonelly-injected hepatocytes migrated and repopulated the lymph nodes, rescuing the animal from lethal hepatic failure. mTORC2 pathway could contribute to ectopic liver organogenesis inducing transplanted cells to migrate to the extrahepatic sites and propagate.
In the above-mentioned study, hepatocytes behave as metastatic cell being able to migrate to the lymph nodes. Therefore, it is likely that a complex network of chemokines and their receptors contributes to the observed ectopic liver organogenesis. Importantly, chemokine receptor/ligand interactions have been shown to activate mTORC1 in some cancer types. Thus, an intricate regulation of the mTOR system could allow hepatocytes to migrate, enter the lymph nodes, be retained and proliferate.
mTOR is also a potential target for liver cancer (HCC) therapy. Although rapamycin -used for years to help prevent rejection of organ transplants- was shown to possess anti-cancer activities, some clinical trials reported contradictory effects, largely attributable to its ability to relieve feedback inhibition from mTORC1 to mTORC2-triggered Akt activation. mTORC2 signaling might contribute to HCC progression and recurrence. Of significant importance could be therefore to understand whether its activity is a feature of primary HCC and HCC metastases and to analyze the effects of blockade of specific components by molecular interference and/or use of mTOR second generation inhibitors in the population of cancer stem cells.
Source RiMED Foundation
Term 03/09/11 – 1/9/12
Amount $74,250