It is proposed that most neoplasms arise from a single cell of origin, and tumor progression results from acquired genetic variability within the original clone allowing sequential selection of more aggressive sublines. Tumor cell populations are apparently more genetically unstable than normal cells, perhaps from activation of specific gene loci in the neoplasm, continued presence of carcinogen, or even nutritional deficiencies within the tumor. The acquired genetic insta0ility and associated selection process, most readily recognized cytogenetically, results in advanced human malignancies being highly individual karyotypically and biologically. Hence, each patient's cancer may require individual specific therapy, and even this may be thwarted by emergence of a genetically variant subline resistant to the treatment. More research should be directed toward understanding and controlling the evolutionary process in tumors before it reaches the late stage usually seen in clinical cancer.

http://science.sciencemag.org/content/sci/194/4260/23.full.pdf

The clonal evolution of tumor cell populations

The biology of cancer: metabolic reprogramming fuels cell growth and proliferation

The concentrations of bases, nucleosides, and nucleosides mono-, di- and tri-phosphate are compared for about 600 published values. The data are predominantly from mammalian cells and fluids. For the most important ribonucleotides average concentrations ±SD (μM) are: ATP, 3,152±1,698; GTP, 468±224; UTP, 567±460 and CTP, 278±242. For deoxynucleosidestriphosphate (dNTP), the concentrations in dividing cells are: dATP, 24±22; dGTP, 5.2±4.5; dCTP, 29±19 and dTTP 37±30. By comparison, dUTP is usually about 0.2 μM. For, the 4 dNTPs, tumor cells have concentrations of 6–11 fold over normal cells, and for the 4 NTPs, tumor cells also have concentrations 1.2–5 fold over the normal cells. By comparison, the concentrations of NTPs are significantly lower in various types of blood cells. The average concentration of bases and nucleosides in plasma and other extracellular fluids is generally in the range of 0.4–6 μM; these values are usually lower than corresponding intracellular concentrations. For phosphate compounds, average cellular concentrations are: Pi, 4400; ribose-1-P, 55; ribose-5-P, 70 and P-ribose-PP, 9.0. The metal ion magnesium, important for coordinating phosphates in nucleotides, has values (mM) of: free Mg2+, 1.1; complexed-Mg, 8.0. Consideration of experiments on the intracellular compartmentation of nucleotides shows support for this process between the cytoplasm and mitochondria, but not between the cytoplasm and the nucleus.

Physiological concentrations of purines and pyrimidines.

Chemistry of biologically important synthetic organoselenium compounds.

Polyamines in rapid growth and cancer

Studies on Morris hepatomas demonstrate that the specific activity of the enzymes of the Leloir pathway are subject to a variation in tumor tissue. The key enzyme of the galactose pathway, uridine diphosphogalactose 4′-epimerase, is elevated 5- to 9-fold in the rapidly growing and poorly differentiated Tumors 3924A and 7777; in line 9618A 2 , an even 28-fold increase was found. The observed correlation between enzyme activity, growth rate, and degree of differentiation of the hepatoma suggests that the differences are not coincidental variations. Conversely, the activity of uridine diphosphoglucose:galactose-1-phosphate uridyltransferase was diminished by 40 to 70% as compared to host liver, and the level of galactokinase showed only minor changes. The uptake of galactose and galactosamine by the hepatoma is heavily impaired, whereas the transport of other hexoses and amino sugars (2-deoxyglucose, l-fucose, N -acetylglucosamine, N -acetylmannosamine) is hardly affected. It appears that part of the carrier-mediated diffusion for hexoses is altered without a decisive impact on the whole system. Moreover, autoradiographic analysis of [ 14 C]galactose-labeled tumor plasma membranes revealed a shift of the incorporation pattern from high- to lower-molecular-weight galactopolypeptides. Our results indicate that specific alterations of the d-galactose metabolism are a characteristic feature of Morris hepatomas.

https://cancerres.aacrjournals.org/content/canres/40/6/2026.full.pdf

Alterations of d-Galactose Metabolism in Morris Hepatomas

Altered subcellular and submitochondrial localization of CTP:phosphatidate cytidylyltransferase in the Morris 7777 hepatoma.

A self-phosphorylating, polylysine-stimulated protein kinase, which was partially purified from the cytosol of fastgrowing Morris hepatoma 3924A, was resolved into a catalytic component and several phosphate acceptor proteins when subjected to a phosphocellulose column. Other chromatographic and electrophoretic procedures were unable to dissociate them. When once dissociated, the catalytic component phosphorylated preferentially casein and nuclear phosphoproteins but not histone and protamine; the component appeared to be one of casein kinases of classical type. With the dissociated phosphate acceptor proteins as substrates, the phosphorylation reaction was stimulated greatly (2- to 10-fold, sometimes more) by the addition of polylysine or H1 histone. These basic polypeptides themselves were not phosphorylated in this reaction. Other histone fractions were less stimulatory. The apparent Ka for polylysine was about 8 µg/ml. When casein was used as phosphate acceptor, less than 2-fold stimulation was observed by the basic polypeptides. The molecular weight of the catalytic component was about 2.1 × 105 as estimated by gel filtration. Km for adenosine triphosphate was 4 × 10-6 m. The pH optimum was 7.5 to 8.5. When the dissociated phosphate acceptor proteins were used, in the absence of polylysine the catalytic component showed a biphasic concentration curve for Mg2+ with optimum concentrations of 50 to 100 mm, whereas in the presence of polylysine the curve was normalized and the reaction proceeded well at lower Mg2+ concentrations. In contrast, when casein was used as phosphate acceptor, the catalytic component was active at 10 to 75 mm Mg2+ in both the presence and the absence of polylysine. Upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the phosphate acceptor proteins showed a major and several minor protein bands; the major protein had an approximate molecular weight of 7 × 104. The results indicate that the catalytic component is associated with its own phosphate acceptor proteins and that the phosphorylation of such phosphate acceptor proteins apparently requires another polycationic factor such as polylysine or histone. The naturally occurring polycationic factor in the cytoplasm has not yet been clarified.

Resolution and properties of the catalytic component and phosphate acceptor proteins of a new protein kinase-substrate complex from Morris hepatoma 3924A.

Summary It was found that one Reuber hepatoma and seven Morris hepatomas with different growth rates and various degrees of differentiation contained pyruvate carboxylase (PC) activity ranging from 3 to 113% of control values. The levels of PC activity in the regenerating liver, spontaneous mouse hepatoma, and host livers of tumor-bearing rats were estimated in the range of normal rat liver. In the group of tumors studied, two hepatomas of intermediate growth rate and four highly and well-differentiated, slow-growing tumors, like rat fetal liver, had negligible or little PC activity. However, one hepatoma, 9618A, had a normal level of PC activity. Antibodies prepared in rabbits against the purified mitochondrial enzyme showed identical titration curves against the nuclear and cytosol PC of liver. A single continuous precipitation line was obtained on Ouchterlony double-diffusion precipitation analysis when purified mitochondrial enzyme, crude mitochondrial preparations of rat tissues and hepatomas, were compared. It was also found that the immunological, enzymatic, and electrophoretic properties of the tumor PC were the same as those of normal adult and newborn rat liver. The amount of enzyme protein was quantitatively reduced in all but one of the liver tumors studied.

https://cancerres.aacrjournals.org/content/canres/33/9/2034.full.pdf

Harold P. Morris

Papers

Alterations of d-Galactose Metabolism in Morris Hepatomas

Altered subcellular and submitochondrial localization of CTP:phosphatidate cytidylyltransferase in the Morris 7777 hepatoma.

Resolution and properties of the catalytic component and phosphate acceptor proteins of a new protein kinase-substrate complex from Morris hepatoma 3924A.

Enzymatic and Immunological Studies on Pyruvate Carboxylase in Livers and Liver Tumors

Studies on the protein binding of N-2-fluorenylacetamide.