Various metabolic studies of human cancer have shown that loss of respiratory function precedes cellular neoplasia and aerobic glycolysis (the Warburg effect).
In addition to the evidence obtained from Warburg, Roskelley and colleagues also elucidated this fact in studies conducted on various animal and human tumor tissues. They used two chemical systems to assess the respiratory function of tumor tissue and the normal host tissue from which it originated. The two chemical systems are represented as follows:
1.O2 - cytochrome oxidase - cytochrome c - p- p-phenylenediamine
2.O2 - cytochrome oxidase - cytochrome c - succinate dehydrogenase Monosuccinate
In most normal cells, these enzyme systems provide the main pathways to achieve important aerobic combustion processes. These pathways can therefore represent a physiological process that can be used to assess the likelihood of a tissue developing tumors. From their results, it is clear that the tumor tissue has severely impaired respiratory function compared to the tumor-free host tissue that breathes normally.
To further explore the mechanisms involved, the researchers followed the progression of liver tumors caused by butter yellow (p-dimethylaminoazobenzene) in rats and in rabbits treated with Schop papillomavirus. Skin cancer progression. Notably, respiratory activity in the treated tissue in both experimental groups initially increased for a few weeks, but then declined rapidly until there was little or no respiratory activity in liver tissue or skin tissue.
Histological evidence of a "definite tumor" associated with the onset of aerobic glycolysis was not present for some time after tissue processing.
Many insights into the origins of cancer came from the studies described above.
First, human cancer tissue does not exhibit normal breathing abilities. Despite differences in the tissue of tumor origin and histological heterogeneity, all tumor cells exhibit hyporespiration.
The second use of chemicals or viruses can induce cancer in animal tissues, and both change the respiration of cells in a similar way. It is now recognized that carcinogenic hydrocarbons, aflatoxins, viruses, and X-rays all impair mitochondrial function and energy metabolism in similar ways. Interestingly, chemical carcinogens and viruses can also activate the oncogene in a similar manner, which means that oncogene activation is secondary to mitochondrial damage.
Most genetic defects found in cancer are not inherited but sporadic. Although germline mutations can increase the risk of some rare tumors, most cancer gene mutations are somatic and may contribute to cancer progression rather than origin.
Interestingly, however, somatic mutations occur only occasionally in cells and tissues. Why is somatic mutation , which rarely occurs in normal tissues, often seen in tumor tissues?
Multiple mutations found in tumor cells are primarily due to mutations in genes responsible for maintaining the fidelity of DNA synthesis or maintaining the adequacy of DNA repair. More specifically, mutations in genome caretaker genes are responsible for the disruption of genome stability and the large number of somatic mutations found in cancer. Mutations in these genes trigger bursts of new mutations throughout the genome.
On the other hand, normal cellular respiration can inhibit tumorigenicity. If mutations in p53, a caretaker gene, are not present in all common human tumors, this suggests a more complex involvement of p53 and other genome guardian genes in tumorigenesis. Although p53 gene mutations are thought to be common in human glioblastoma multiforme , p53 gene defects are not found in approximately 60% of these tumors. Although a large number of abnormal genes have been identified in most human cancers, no specific mutations can reliably diagnose any particular type of tumor.
In most tumors of non-reproductive origin, the mutations of various tumor cells are different from each other. So how can gene mutations be said to be the common origin of cancer? These findings suggest that most tumor-associated somatic mutations are neither necessary nor sufficient to cause cancer.
Although common somatic mutations exist in some tumors, it is unlikely that these mutations are expressed in every cell of the tumor due to cellular and genetic heterogeneity. However, interestingly, patients with slow progression of malignant glioma usually have combined chromosome 1p/19q deletions, O6-methylguanine methyltransferase (MCMT) gene promoter hypermethylation, and IDH1 gene mutations. Can we consider tumors with these mutations to be “better” just because they progress much more slowly than tumors without them? At the same time, we also found that CBM patients with 1D111 mutations survived slightly longer than those without this mutation.
Based on the above information, it is difficult for us to regard cancer-related gene mutations as the origin of cancer. Therefore, it is necessary to re-examine the key evidence that oncogenes are the origin of cancer. According to Michael Stratton, transplanting the entire genome DNA of human cancer cells into normal NIH3T3 cells will transform them into cancer cells, which is key evidence for the theory of the origin of cancer oncogenes. He cites the paper by Krontiris and Cooper as evidence. However, the fact is that high-molecular-weight DNA from bladder cancer cells in only 2 of the 24 cancer types can transform NIH3T3 cells into cancer cells, and the authors cannot rule out the possibility that the cell transformation results from viral infection.
Reference:
"Cancer is a metabolic disease - On the origin, treatment and prevention of cancer"
Author: Thomas N. Disease
