Summary
Cancer is not a result of a single genetic alteration, but it occurs when there are many mutations in a genome. It does not depend only on the genomic mutations but also on some other factors that stimulate the tumors to result. The genetic alterations vary in different types of cancer and even in a similar type of cancer. Different patients of the same type of cancer have different genomes. This is termed tumor heterogeneity. But all the cancer cells have the same glucose metabolism that is higher than the neighboring normal cells. So, to cure cancer, we need to target their sugar metabolic pathway. For this, a glucose analog 2-deoxy-D-glucose is being used that not only inhibits the glycolytic pathway but also changes the expression of many genes, whose transcription is vital for the growth and survival of cells. Many experiments have been performed in this regard that will be discussed in this article to prove that 2DG has cut tumor heterogeneity.
Introduction
Cancer is found to be a heterogenetic disorder, showing multiple types of variations in the genome of the same patient, making it a very complex disorder. Moreover, it is found recently that patients suffering from the same type of cancer not only have different genomic mutations but also different morphological and physiological characteristics. This is commonly termed Tumor Heterogeneity (Holland & Cleveland, 2009).
Tumor heterogeneity is observed in almost all types of cancer. It may have resulted from the imperfect DNA replication process during cell division. When cells are dividing, some mutations are acquired by the daughter cells, that later, result in any type of cancer after receiving stimulus from the environment. The genome of such patients is very complex. But it is paving the way in cancer research to understanding the genetic bases of different cancer types as well as helping in cancer therapeutics. Many compounds are being discovered that can target these genetically mutated proteins and help in the killing of malignant cells (Kemper et al., 2015).
Types of Tumor heterogeneity
Tumor heterogeneity can be classified into two types.
1. Spatial tumor heterogeneity
It is the random distribution of cancer cells across the affected tissue.
2. Temporal tumor heterogeneity
The initial tumor keeps on changing into different subclones with the passage of time. This is termed temporal heterogeneity.
Tumor heterogeneity is resulting in the resistance of cancer cells toward available therapeutic modalities. So, the need of the hour is to find some therapeutic strategy that can help overcome this resistance caused by the complex genome of malignant cells (Kemper et al., 2015).
Causes of tumor heterogeneity
The main cause of tumor heterogeneity is the instability of the genome which ranges in magnitude from a single base alteration to the doubling of even the whole genome. This large-scale instability is resulting in the formation and metastasis of many different types of tumors. This genomic instability may be the result of some extrinsic cause factors or intrinsic factors. Sequencing techniques like sanger sequencing and Next-generation Sequencing have made it easy to find out the genomic alterations and to sequence the complete genome of the control as well as patient for comparison. This genome sequencing has introduced tumor heterogeneity (Holland & Cleveland, 2009).
Clonal evolution hypothesis
According to this hypothesis, the instability of the genome results in many genetic and epigenetic alterations with the passage of time increasing genomic diversity. This tumor heterogeneity leads to mutations in different regions of the genome of a person making it difficult to find the root cause or driver mutation that is actually responsible for the causation of this tumor. It also causes the spread of tumors to different body regions. Genomic instability or heterogeneity also leads to the formation of many competitive subclones. But increased levels of genetic heterogeneity may have harmful or adverse effects on the survival of cancer cells and their metastasis to the neighboring tissues.
Tumors are not only caused by genetic heterogeneity, but they also need some other factors along with genomic mutations. That helps them to grow and proliferate rapidly.
These findings discussed until now show that cancer cells can have different genomes because the variations in the genome of cancer cells vary from patient to patient. Even patients with the same type of cancer have different genetic mutations responsible for causing the disease (Dagogo-Jack & Shaw, 2018).
Glucose metabolism in cancer cells
But all cancer cells having any kind of genetic alteration require a large amount of energy for their growth, proliferation, and metastasis to the neighboring tissues. Hence, they need to take a greater amount of energy in the form of glucose from the environment by GluT1 transporters that are then converted to ATP by glycolysis. Tumor cells undergo glycolysis even in the presence of oxygen just to produce more ATP that is necessary for their survival. Hence, the sugar metabolism in all the cancer cells is the same regardless of what kind of genome they have (Aft et al., 2002).
In order to treat patients suffering from any type of cancer, and whatever genomic alteration is the driver mutation against the disorder, we need to target the glycolytic pathway, as glucose metabolism is the same in all types of cancers (Jordan et al., 2017). To target the glycolytic pathway, we need some inhibitor or glucose antimetabolite having structural similarity with glucose. 2-deoxy-D-glucose is an important glycolytic inhibitor that makes the cancer cells deprived of nutrients and hence the cells cannot survive under these conditions of malnutrition. The mechanism of action of 2DG in tumor cells is shown in the figure (Arora et al., 1992).
Mechanism of action of 2DG
Fluorine-18 is a radiolabel that is used for 2DG. 2DG is used as an investigational drug to determine the sugar metabolism in cancer cells. It is usually associated with the Positron Emission Tomography (PET) scan technique. 2DG also activates the apoptotic pathway in cancer cells (Aft et al., 2002).
2DG inhibits the glycosylation of proteins and lipids within the cancer cells. This results in the misfolding of proteins. When proteins are not properly folded, they will not be able to perform their normal function in a cell. These proteins will not activate the downstream proteins of their pathways and the whole pathway in that cell gets disrupted. This also affects the expression of many genes that are transcribed by these transcription factor proteins. So, the whole biochemical process in a cell is damaged. This will not allow the cancer cells to proliferate or grow anymore (Aft et al., 2002).
Experimental Findings
Many experiments have been performed in vitro, in vivo, and in humans to study the complete mechanism of 2DG on cells. It is found that 2DG not only inhibits glycolysis in cells, but it also activates apoptosis without any harm to normal cells. In addition to this, 2DG changes the gene expression regulation within cells that do not allow transcription factors to transcribe important genes required for the growth and proliferation of cells. Thus, 2DG can be used to cut the heterogeneity of all the cancer cells.
Cancer cells can have different genetic alterations that are the drifting cause of disease. But as they have the same sugar metabolism, which is far greater than that in normal cells, 2DG can be used as a standard therapy to treat all cancer types. Because 2DG not only make the cells deprived of oxygen but also changes the gene expression regulation in these cells, inhibiting their growth and proliferation, and making them ready for apoptosis (Dagogo-Jack & Shaw, 2018).
Conclusion
Cancer cells have different types of mutations in their genes, either missense, nonsense, frameshift, or splice site mutations. There always a driver mutation that is mainly responsible for the causation of the disorder, but all the other alterations are also played some role. These different mutations even in patients suffering from the same type of cancer make the disease more complex. But it also helps cancer geneticists in their research to find the root cause of the disorder and target that cause for a cure.
Although cancer cells have different types of mutations, all cancer cells need a large amount of energy for their growth and survival. And so they need a large amount of glucose for ATP production.
In order to treat cancers having large heterogeneity, we need some standard therapy that can be used for any type of cancer even if we don’t know the root cause. For this purpose, we need to make these cells deprived of glucose and nutrients. And we need to use some glucose antimetabolite like 2DG which is a glucose analog. It not only makes the cells deprived of glucose or ATP, but it also inhibits the growth of cells by inhibiting the transcription of many genes or by changing their expression. When these genes are not transcribed, their proteins will not be formed, and hence no function related to the growth of the cell will be performed. Thus, cancer cells will not be able to grow and metastasize to other tissues.
References
Aft, R. L., Zhang, F. W., & Gius, D. (2002). Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: Mechanism of cell death. British Journal of Cancer, 87(7), 805–812. https://doi.org/10.1038/sj.bjc.6600547
Arora, K. K., Parry, D. M., & Pedersen, P. L. (1992). Hexokinase receptors: Preferential enzyme binding in normal cells to nonmitochondrial sites and in transformed cells to mitochondrial sites. Journal of Bioenergetics and Biomembranes, 24(1), 47–53. https://doi.org/10.1007/BF00769530
Dagogo-Jack, I., & Shaw, A. T. (2018). Tumour heterogeneity and resistance to cancer therapies. Nature Reviews Clinical Oncology, 15(2), 81–94. https://doi.org/10.1038/nrclinonc.2017.166
Holland, A. J., & Cleveland, D. W. (2009). Boveri revisited: Chromosomal instability, aneuploidy, and tumorigenesis. Nature Reviews Molecular Cell Biology, 10(7), 478–487. https://doi.org/10.1038/nrm2718
Jordan, E. J., Kim, H. R., Arcila, M. E., Barron, D., Chakravarty, D., Gao, J. J., Chang, M. T., Ni, A., Kundra, R., Jonsson, P., Jayakumaran, G., Gao, S. P., Johnsen, H. C., Hanrahan, A. J., Zehir, A., Rekhtman, N., Ginsberg, M. S., Li, B. T., Yu, H. A., … Riely, G. J. (2017). Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discovery, 7(6), 596–609. https://doi.org/10.1158/2159-8290.CD-16-1337
Kemper, K., Krijgsman, O., Cornelissen‐Steijger, P., Shahrabi, A., Weeber, F., Song, J., Kuilman, T., Vis, D. J., Wessels, L. F., Voest, E. E., Schumacher, T. N., Blank, C. U., Adams, D. J., Haanen, J. B., & Peeper, D. S. (2015). Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts. EMBO Molecular Medicine, 7(9), 1104–1118. https://doi.org/10.15252/emmm.201404914
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