One signal that is overactivated in a wide range of tumour types is the production of a phospholipid, phosphatidylinositol (3,4,5) trisphosphate, by phosphatidylinositol 3-kinase (PI3K) This lipid and the protein kinase that is activated by it — AKT — trigger a cascade of responses, from cell growth and proliferation to survival and motility, that drive tumour progression Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype

The phosphatidylinositol 3-Kinase AKT pathway in human cancer.

Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Genetic alterations affecting p16(INK4a) and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein (RB) and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development. Like the tumor suppressor protein p53, components of this "RB pathway," although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life.

http://science.sciencemag.org/content/sci/274/5293/1672.full.pdf

Cancer Cell Cycles

Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.

http://science.sciencemag.org/content/sci/321/5897/1807.full.pdf

An Integrated Genomic Analysis of Human Glioblastoma Multiforme

Background A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). Methods We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. Results We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations h...

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IDH1 and IDH2 Mutations in Gliomas

p53, guardian of the genome

20-( S )-Camptothecin (CAM), a plant alkaloid, was tested against 13 human cancer xenograft lines carried by immunodeficient (nude) mice. The drug, formulated in 20% intralipid and given i.m., was more effective than any other clinically available drug tested. It was found that: ( a ) CAM, at nontoxic doses, suppressed growth and induced regression of cancer of the colon (3 lines), lung (4 lines), breast (2 lines), stomach (1 line), ovary (1 line), and malignant melanoma (2 lines); ( b ) the drug was equally effective administered i.m. or p.o. Both routes are significantly better than i.v. administration; ( c ) CAM is substantially more effective and less toxic than its sodium salt, which was unsuccessfully tested in cancer patients. CAM should be further tested against responsive cancers as a drug which is easy to isolate and formulate for large-scale studies.

https://cancerres.aacrjournals.org/content/canres/51/11/3052.full.pdf

Complete Growth Inhibition of Human Cancer Xenografts in Nude Mice by Treatment with 20-(S)-Camptothecin

Human hematopoietic cell lines, which had been classified on the basis of studies on clonality, and morphological, chromosomal and functional parameters as lymphoblastoid cell lines (LCL) of presumed non-neoplastic origin, and lymphoma, myeloma and leukemia lines of proven malignant origin, were tested for tumorigenic potential on subcutaneous transplantation to nude mice and for capacity to grow in semi-solid medium in vitro. Recently established LCL failed to grow both in nude mice and in agarose. In contrast, some of the LCL which had developed secondary chromosomal alterations during continuous cultivation for periods exceeding several years were tumorigenic and/or had the capacity to form colonies in agarose. Most lymphoma lines formed colonies in agarose and tumors in the mice. One of the two myeloma lines formed subcutaneous tumor which, however, showed no progressive growth. The other myeloma line failed to grow. Both myeloma lines, however, formed colonies in agarose. The myeloid leukemia line was tumorigenic while two of the three tested lymphocytic leukemia lines failed to grow in the mice. All leukemia lines formed colonies in agarose. We conclude from this study that: (1) Of the two types of Epstein-Barr virus containing cell lines [LCL and Burkitt lymphoma (BL) lines], only BL lines were shown to form tumors when inoculated subcutaneously in nude mice and had the capacity to grow in agarose in vitro. This shows that EBV transformation per se does not necessarily render lymphocytes tumorigenic in nude mice. The capacity to form colonies in agarose is not acquired either. (2) Changes of the karyotype and several phenotypic characteristics which occur in the originally diploid LCL during prolonged cultivation in vitro may be accompanied by the acquisition of the potential to grow subcutaneously in nude mice and in agarose in vitro. (3) The inconsistency with regard to the capacity of come of the neoplastic cell lines to grow in nude mice or in agarose seems to underline that neither of the two tests is a reliable criterion for malignancy of human lymphoma, leukemia and myeloma cell lines.

Tumorigenicity of human hematopoietic cell lines in athymic nude mice

Summary The effects of supranormal temperatures upon normal human cells (derived from normal adult and embryonal tissues) and neoplastic human cells (derived from biopsies of malignant tumors) have been quantitatively studied in tissue culture. Melanoma cells have been compared with melanocytes derived from fetal uveas. Colon carcinoma cells have been compared with embryonal intestinal epithelial cells. Malignant neuroepithelial cells derived from a teratocarcinoma of the ovary have been compared with neuroepithelial cells derived from fetal brain. Fibrosarcoma cells have been compared with normal adult fibroblasts. All cells defined as neoplastic have produced malignant tumors when injected into nude thymus-deficient mice at doses of 1 × 10 7 cells or less. Exposure to temperatures of 42.5-43.0° for 4 to 8 hr has been shown to have significantly greater lethal effect on the tumor cells than on the nonneoplastic cells.

https://cancerres.aacrjournals.org/content/canres/36/11_Part_1/3944.full.pdf

Selective lethal effect of supranormal temperatures on human neoplastic cells.

More than 200 human cancers have been successfully transplanted into nude athymic mice in our laboratory. Strict sterile techniques must be applied in caring for these animals and meticulous attention given to the preparation of the surgical specimens. That the tumors remain human in the mice has been documented by isozyme and karyotype analyses. Also, histopathologic comparisons between the original human tumors and their transplanted counterparts in the mice are strikingly similar or identical. Preliminary results of chemotherapy of human cancers in the nude mice are extremely encouraging. At this point, we believe that the greatest potential for the nude mice lies in their use in testing anticancer therapies for human neoplasms without placing the patients at risk.

Heterotransplantation of human cancers into nude mice: a model system for human cancer chemotherapy.

Summary The effects of supranormal temperatures upon normal (derived from normal, embryonal tissues) and neoplastic (derived from 3-methylcholanthrene-induced sarcomas) mesenchymal cells from C57BL/6 mice have been quantitatively studied in tissue culture. It has been found that exposure to a temperature of 42.5° for 2 hr or more has a selective lethal effect upon tumor cells (defined as cells capable of developing into a malignant tumor when injected into syngenic mice at doses of 1 × 10 6 cells or less in adults or 1 × 10 5 or less in newborns). No other biological characteristic studied (aneuploidy, length of time in culture, and rate of growth) could be correlated significantly with thermosensitivity. All the cultures of tumor-derived and tumor-producing cells exhibited the same high degree of thermosensitivity, i.e. , death of 95% of the cells after 2 hr exposure at 42.5°. All the cultured normal, nontumor-producing cells exhibited a lower degree of heat sensitivity, i.e. , death of 43% of the cells after 2 hr exposure to 42.5°. When a cell subline having a high tumor-producing ability was derived from a nontumor-producing line, it acquired a greater thermosensitivity, although its rate of growth was the same as that of the original line. These results indicate that the acquisition of biological malignant potential, both in vitro and in vivo , is accompanied by increased thermosensitivity in mouse mesenchymal cells.

Beppino C. Giovanella

Papers

Complete Growth Inhibition of Human Cancer Xenografts in Nude Mice by Treatment with 20-(S)-Camptothecin

Tumorigenicity of human hematopoietic cell lines in athymic nude mice

Selective lethal effect of supranormal temperatures on human neoplastic cells.

Heterotransplantation of human cancers into nude mice: a model system for human cancer chemotherapy.

Selective lethal effect of supranormal temperatures on mouse sarcoma cells.