Although cancer classification has improved over the past 30 years, there has been no general approach for identifying new cancer classes (class discovery) or for assigning tumors to known classes (class prediction). Here, a generic approach to cancer classification based on gene expression monitoring by DNA microarrays is described and applied to human acute leukemias as a test case. A class discovery procedure automatically discovered the distinction between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) without previous knowledge of these classes. An automatically derived class predictor was able to determine the class of new leukemia cases. The results demonstrate the feasibility of cancer classification based solely on gene expression monitoring and suggest a general strategy for discovering and predicting cancer classes for other types of cancer, independent of previous biological knowledge.

/pdf/molecular-classification-of-cancer-class-discovery-and-class-22p4huwudl.pdf

Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.

Future cell-based therapies such as tissue engineering will benefit from a source of autologous pluripotent stem cells. For mesodermal tissue engineering, one such source of cells is the bone marrow stroma. The bone marrow compartment contains several cell populations, including mesenchymal stem cells (MSCs) that are capable of differentiating into adipogenic, osteogenic, chondrogenic, and myogenic cells. However, autologous bone marrow procurement has potential limitations. An alternate source of autologous adult stem cells that is obtainable in large quantities, under local anesthesia, with minimal discomfort would be advantageous. In this study, we determined if a population of stem cells could be isolated from human adipose tissue. Human adipose tissue, obtained by suction-assisted lipectomy (i.e., liposuction), was processed to obtain a fibroblast-like population of cells or a processed lipoaspirate (PLA). These PLA cells can be maintained in vitro for extended periods with stable population doubling and low levels of senescence. Immunofluorescence and flow cytometry show that the majority of PLA cells are of mesodermal or mesenchymal origin with low levels of contaminating pericytes, endothelial cells, and smooth muscle cells. Finally, PLA cells differentiate in vitro into adipogenic, chondrogenic, myogenic, and osteogenic cells in the presence of lineage-specific induction factors. In conclusion, the data support the hypothesis that a human lipoaspirate contains multipotent cells and may represent an alternative stem cell source to bone marrow-derived MSCs.

/pdf/multilineage-cells-from-human-adipose-tissue-implications-4z32vwpf0q.pdf

Multilineage cells from human adipose tissue: implications for cell-based therapies.

The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.

mTOR Signaling in Growth Control and Disease

mTOR signaling in growth control and disease.

https://archive-ouverte.unige.ch/unige:18229/ATTACHMENT01

TOR signaling in growth and metabolism.

Rapamycin, a macrocyclic lactone, is a highly specific inhibitor of the serine/threonine protein kinase target of rapamycin (TOR). Although it is clear that TOR controls initiation of protein translation, recent results indicate that TOR is a central controller, integrating a plethora of signalling pathways that respond to growth factors and nutritional status. In addition to the role of rapamycin as an immune suppressant, emerging data indicate that genetic and metabolic changes accompanying malignant transformation might cause hypersensitivity to TOR inhibition.

The tor pathway: a target for cancer therapy

The immunosuppressant rapamycin interferes with G1-phase progression in lymphoid and other cell types by inhibiting the function of the mammalian target of rapamycin (mTOR). mTOR was determined to be a terminal kinase in a signaling pathway that couples mitogenic stimulation to the phosphorylation of the eukaryotic initiation factor (eIF)-4E-binding protein, PHAS-I. The rapamycin-sensitive protein kinase activity of mTOR was required for phosphorylation of PHAS-I in insulin-stimulated human embryonic kidney cells. mTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. These studies define a role for mTOR in translational control and offer further insights into the mechanism whereby rapamycin inhibits G1-phase progression in mammalian cells.

https://science.sciencemag.org/content/sci/277/5322/99.full.pdf

Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin

Heterotransplantation of human cancer cells or tumor biopsies into immunodeficient rodents (xenograft models) has, for the past two decades, constituted the major preclinical screen for the development of novel cancer therapeutics. Despite limitations, these models have identified clinically efficacious agents, and remain the 'workhorse' of the pharmaceutical industry. However, if therapeutic approaches to treating tumors according to their molecular characteristics are to be achieved, additional new models of human cancer will be required to represent the genetic diversity that exists within tumor histologies. This protocol details a method for establishing xenografts from primary solid-tumor isolates or cells grown in culture. The procedure relies on immunodeficient mice to provide a host for the establishment of human xenografts. The procedure can be completed in 1–2 h with results being obtained in 1–4 months.

/pdf/establishment-of-human-tumor-xenografts-in-immunodeficient-31ura2pd95.pdf

Establishment of human tumor xenografts in immunodeficient mice.

Targeting mTOR signaling for cancer therapy.

Proteins regulating the mammalian target of rapamycin (mTOR), as well as some of the targets of the mTOR kinase, are overexpressed or mutated in cancer. Rapamycin, the naturally occurring inhibitor of mTOR, along with a number of recently developed rapamycin analogs (rapalogs) consisting of synthetically derived compounds containing minor chemical modifications to the parent structure, inhibit the growth of cell lines derived from multiple tumor types in vitro, and tumor models in vivo. Results from clinical trials indicate that the rapalogs may be useful for the treatment of subsets of certain types of cancer. The sporadic responses from the initial clinical trials, based on the hypothesis of general translation inhibition of cancer cells are now beginning to be understood owing to a more complete understanding of the dynamics of mTOR regulation and the function of mTOR in the tumor microenvironment. This review will summarize the preclinical and clinical data and recent discoveries of the function of mTOR in cancer and growth regulation.

http://dipbsf.uninsubria.it/monti/BFPN%202009/1209886a.pdf?origin=publication_detail

Peter J. Houghton

Papers

The tor pathway: a target for cancer therapy

Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin

Establishment of human tumor xenografts in immunodeficient mice.

Targeting mTOR signaling for cancer therapy.

mTOR and cancer therapy.