Cancer and transplantation intersect at the mammalian target of rapamycin.

The paper by Gomez-Camerero et al. in this issue, “Use of everolimus as a rescue immunosuppressive therapy in liver transplantation,” adds to a growing literature on mammalian target of rapamycin (mTOR) inhibitor use in cancer. It is of interest because of the spectrum of cancers treated and because of the comparison to a similar group of cancers in liver recipients not switched. All 10 patients switched from a calcineurin inhibitor (CNI) to everolimus (EVR) had remissions. Despite three deaths (two not from cancer), the average survival exceeded 20 months compared to 5.3 months in controls. Both groups had conventional treatments (surgery, radiation, and chemotherapy). Rapamycins are as immunosuppressive as CNIs, yet they reduce the risk of cancer in transplant recipients compared to CNIs (1) and they appear useful for treating new cancers. Unraveling the actions of rapamycin has increased our understanding of growth pathways of normal and cancer cells. Growth factors including insulin-like growth factor-1, platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) stimulate cell growth and division by initiating a cascade of events beginning when they engage their receptors. This results in activation of phosphotidyl-inositol-3 kinase (PI3K), which converts PIP2 to PIP3, a step inhibited by PTEN (Phosphatase and Tensin homologue, mutated or deleted in many cancers). PIP3 attracts PDK1 and Akt (protein kinase B) to the membrane and they in turn uncouple an inhibitor complex TSC1/TSC2 (tuberous sclerosis complex 1/ 2) releasing Rheb (Ras homolog enriched in brain) a GTPase which then activates mTOR. mTOR integrates this signaling pathway with amino acid availability and the energy status of the cell and controls translation initiation through phosphorylation activation of the ribosomal protein S6 kinase and in turn of ribosomal protein S6 increasing ribosomal generation. It also phosphorylates 4E-binding protein 1 (4E-BP-1), releasing its inhibitory effect on the eukaryotic initiation factor 4E (eIF4E) an activator of cyclins and their kinases (Fig. 1). Cyclin-D levels rise as well as its regulator p21. p21 facilitates the assembly of a complex containing cyclins, cyclin-dependant kinases, p21, and proliferating cell nuclear antigen (PCNA); this complex catalyzes Rb (retinoblastoma protein) phosphorylation releasing its inhibition of cell-cycle progression. Rapamycin can decrease p21 synthesis and increase the levels of p27, an inhibitor of cdks. This effect can be reversed by an excess of cyclin-D and cancers that have overexpression of cyclin-D should be insensitive to mTOR inhibition. p53 as the guardian protecting cells from inappropriate growth is intimately involved in the mTOR pathway including augmentation of the inhibitory actions of PTEN and indirectly of TSC1/2. Elimination of p53 activity is the commonest cancer perturbation and this often keeps the Akt/ mTOR pathway in overdrive. mTOR itself inhibits p53 by promoting the translation of Mdm2, a negative regulator of p53. Adequate oxygenation is another prerequisite for cell division. Hypoxia-inducible factor (HIF), a transcription factor for VEGF, whose concentration is normally reduced by a product of the Von Hippel-Lindau gene (mutated in many cancers), is overexpressed in hypoxic tumors. It acts on TSC 1/2, upregulating mTOR which in turn results in excess production of both VEGF and its receptor and other angiogenic stimulators PDGF, TGFalpha, and FGF, all blocked by rapamycins. Growth factor driven Akt activation accumulates glucose transporters to the cell membrane independently of mTOR but mTOR controls glucose levels. Thus the important signals that tell a cell to grow and divide—as well as those telling it that it has the wherewithal to do so (amino acids, energy from glucose, and oxygen)— converge through mTOR. Rapamycin blocks mTOR preventing cell-cycle progression from G-1 to S. Cancer increases activity in these pathways, or subverts the control factors that normally constrain them. Two of Gomez-Camarero et al.’s patients developed Kaposi’s sarcoma. The causative herpes virus (KSHV) encodes an oncogene which is incorporated into the genome of infected cells inducing the appearance of a ligand-independent G-protein receptor (vGPCR) at the cytoplasmic membrane. It is constitutively active and it turns on the Akt/mTOR pathway. vGPCR is present in only a few cells in Kaposi’s lesions but all its cells express elevated Akt. Activation of Akt/mTOR induces the secretion of angiogenic factors especially VEGF which then acts in an autocrine and paracrine manner to induce cell growth and VEGF production both in infected cells and Department of Surgery, Dalhousie University Halifax, Nova Scotia, Canada. Address correspondence to: Allan S. MacDonald, M.D., FRCSC, Cumberland Regional Health Care Centre, 19428 Hwy 2, Upper Nappan, Nova Scotia B4H 1N6, Canada. E-mail: allan.macdonald@dal.ca Received 31 May 2007. Accepted 4 June 2007. Copyright © 2007 by Lippincott Williams & Wilkins ISSN 0041-1337/07/8406-682 DOI: 10.1097/01.tp. 0000280548.99241. c4