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

Summary The behavior of carbohydrate enzymes was examined in a spectrum of hepatomas of different growth rates, and results were evaluated in the light of data obtained in Hepatoma 5123-D and the Novikoff tumor. The studied biochemical parameters can be classified according to their relation to hepatoma growth rate. There are factors which correlate, others which do not correlate, and, finally, parameters which are decreased or increased in all or most of the tumors. Marked differences in cellularity, nitrogen content, and enzyme activities were found between normal livers and host livers. Therefore, the values of hepatomas were compared with those of normal livers. Certain metabolic features were correlated with the growth rate of liver tumors. Nitrogen content showed a trend to decrease with increasing growth rate, with lowest values found in the rapidly growing tumors. Glucose-6-phosphatase and fructose-1,6-diphosphatase activities in slowly growing tumors were one-half to one-third of normal liver values, and they further decreased in more rapidly growing tumors with no activities in the fastest growing hepatomas. No correlation with growth rate was noted for cellularity or for the enzymes, phosphohexose isomerase, lactic dehydrogenase, and 6-phosphogluconate dehydrogenase. Phosphoglucomutase was significantly decreased in all examined tumors. In contrast, glucose-6-phosphate dehydrogenase was increased in all hepatomas with the exception of 5123-D. The presented results were evaluated in terms of the molecular basis and possible biochemical grading of hepatomas exhibiting different biological behavior.

https://cancerres.aacrjournals.org/content/canres/23/7_Part_1/987.full.pdf

Comparative biochemistry of hepatomas. iii. carbohydrate enzymes in liver tumors of different growth rates.

Summary The metabolic fate of labeled fructose and glucose was compared in normal liver and in hepatomas of different growth rates. For certain biochemical parameters a rough correlation with the growth rates of liver tumors was observed. The metabolic disposition of both fructose and glucose was in the same range in the control tissues, and no strain difference could be discerned. The fructose uptake was decreased to 48 per cent or less in all hepatomas. The CO 2 production was decreased to 67 per cent or less. Very little glycogen synthesis from fructose occurred in the slowly growing tumors; however, incorporation was normal or increased in the rapidly growing ones. There was a tendency to decreased glucose production, and all glucose release values were 11 per cent or less of those of the normal. The initial glycogen levels in all tumors were markedly less than those observed in livers of control animals. Lactate production was less than normal in the slowly growing tumors, with normal or slightly increased values in the rapidly growing ones. The maximum glucose phosphorylation was decreased in the examined tumors, with the exception of H-35. The oxidation of C-1 as well as C-6 of glucose showed a tendency to increase parallel with the increase in growth rate of the hepatomas. The C-1/C-6 ratio in CO 2 was in the normal range in the slowly growing tumors but was increased in the rapidly growing hepatomas. The glucose to glycogen ratio also increased with the increased growth rate. The net lactate production observed with glucose present as added substrate was normal for H-35, but in the more rapidly growing hepatomas was markedly increased roughly parallel with the increasing growth rate of the tumors.

https://cancerres.aacrjournals.org/content/canres/23/7_Part_1/995.full.pdf

Comparative Biochemistry of Hepatomas IV. Isotope Studies of Glucose and Fructose Metabolism in Liver Tumors of Different Growth Rates

Continued administration of several hepatocarcinogens led to an increase in the concentration of glutathione (GSH) in the livers of intact, but not of hypophysectomized or adrenalectomized rats. The concentration of GSH remained high untill the development of hyperplastic nodules. Subsequently, the concentration of GSH dropped to the normal level or below. A single dose of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) produced an increase of GSH which, within a certain range, depended upon the amount of the carcinogen. In well differentiated, slowly growing hepatomas, the concentration of GSH approached the level in normal adult rat liver. On the other hand, in nondifferentiated and rapidly growing hepatomas, GSH was only 30-40% of that in normal liver. The activity of gamma-glutamyl transpeptidase (GTase) increased within 24-48 hours after a single large dose of 3'-Me-DAB. Continued feeding of 3'-Me-DAB led to an exponential increase of GTase. During hepatocarcinogenesis, the level of GTase activity corresponded to the degree and size of pathologic changes produced in rat liver. Chloramphenicol partially inhibited the increase of GTase induced by 2-acetylaminofluorene. Pretreatment with 3-methylcholanthrene partially inhibited the increase of GTase that had been induced by a single dose of 3'-Me-DAB. Puromycin partially inhibited the increase of GTase induced by several doses of dimethylnitrosamine. These observations indicated a close connection between the activation of GTase and chemical carcinogenesis in rat liver. Measurements of GTase activity in 12 Morris hepatomas supported this conclusion; their GTase levels were greatly elevated compared with that in normal adult rat liver.

Glutathione and Gamma Glutamyl Transpeptidase in Rat Liver During Chemical Carcinogenesis

Total superoxide dismutase (SOD) and manganese superoxide dismutase (Mn SOD) specific activities were measured in tissue homogenates and in isolated mitochondria from normal rat liver and three Morris hepatomas of different growth rates. Total SOD and Mn SOD specific activities were decreased in all tumor homogenates when compared to normal liver; the lowest activity was associated with the fastest growing tumor. These results are consistent with the hypothesis that total Mn SOD specific activity is decreased in all tumors. The Mn SOD specific activity was similar to the total SOD specific activity of isolated mitochondria, indicating that mitochondrial SOD is almost entirely manganese containing. This activity was decreased in the fast- and medium-growth-rate hepatomas but was slightly increased in the tumor with the slowest growth rate when compared to liver. The normal or higher than normal mitochondrial Mn SOD specific activity indicates that decreased mitochondrial SOD specific activity is not a characteristic of all tumors. Superoxide radical O 2 ⨪ formation was measured in submitochondrial particles obtained by sonication of isolated mitochondria and subsequent washings to remove the SOD. The difficulty encountered in reducing the SOD activity suggests that at least part of the mitochondrial SOD might be associated with the mitochondrial membrane. In liver submitochondrial particles, O 2 ⨪ was formed only when succinate and antimycin A were used together, as substrate and inhibitor of the electron transport chain, respectively. In the hepatomas studied for O 2 ⨪ production (slow- and fast-growth rates), the formation of the radical was detected in the presence of succinate even when no inhibitor was present. Antimycin A stimulated the production of O 2 ⨪ in normal rat liver and slow-growth-rate tumor, but not in fast-growth-rate tumor submitochondrial particles. Reduced nicotinamide adenine dinucleotide did not lead to the production of O 2 ⨪ by normal liver or hepatoma submitochondrial particles. Mitochondrial membrane damage was seen in micrographs of the medium- and fast-growing hepatomas. This could be a consequence of low mitochondrial SOD concomitant with a flux of superoxide, if the radical is produced in vivo by these mitochondria.

/pdf/superoxide-dismutase-and-superoxide-radical-in-morris-kfrui5pogj.pdf

Superoxide Dismutase and Superoxide Radical in Morris Hepatomas

Summary Chromosome studies were done on 35 transplantable rat hepatoma lines, including a number of “minimal deviation” tumors. Cell suspensions were obtained directly from the solid neoplasms by trypsinization, and tumor metaphases were distinguished from contaminating host metaphases by sex chromosome differences. Six tumor lines had a normal chromosome number—42—but only 9618A had a completely normal karyotype. Minimal abnormalities, which could represent normal karyotype variation, were observed in 4 others (7794A, 7800, 9098, 9121), and 9108 had definite changes involving several small chromosomes. This tumor also showed 50% transition to 43 chromosomes in a later transplant generation. The six diploid tumors had an intermediate growth rate and variable enzyme alterations. The 29 aneuploid tumors all had different karyotypes with no obvious correlation between specific chromosome alterations and specific enzyme changes. Some of these tumors were less deviated metabolically than the diploid neoplasms (e.g., 7793, 45 chromosomes) and some were slower growing (e.g., 7787, 44 chromosomes). Chromosome studies will permit identification of tumors which are “minimally deviated” from a cytogenetic standpoint, but a variety of metabolic alterations may still be present.

https://cancerres.aacrjournals.org/content/canres/27/9/1565.full.pdf

Harold P. Morris

Papers

Comparative biochemistry of hepatomas. iii. carbohydrate enzymes in liver tumors of different growth rates.

Comparative Biochemistry of Hepatomas IV. Isotope Studies of Glucose and Fructose Metabolism in Liver Tumors of Different Growth Rates

Glutathione and Gamma Glutamyl Transpeptidase in Rat Liver During Chemical Carcinogenesis

Superoxide Dismutase and Superoxide Radical in Morris Hepatomas

Chromosomes of “Minimal Deviation” Hepatomas and Some Other Transplantable Rat Tumors