Cancer has baffled mankind for a variety of reasons. It is a malady that arises from within – from inside our very own cells – and not from outside of the body, although onset of some cancer types, such as cervical cancer, is linked to viral infections. Unlike other diseases, which tend to stress cells and cause them to not function properly or even die, cancer causes cells to proliferate. Therapeutic strategies therefore target killing cells rather than saving them or repairing their functions. In the strictest sense, cancer has no cure. No one can guarantee that a cancer, once remitted via treatment, will not come back or will not have side effects. In spite of unprecedented money spent on cancer research, medical community is yet to come close to finding a cure. Continuing reliance on the age-old approach of “slash-poison-burn” for cancer treatment has frustrated the likes of Azra Raza who seek a shift in cancer research focus to detection of the first signs of cancer rather than finding a cure1. Finding the root cause is the key to solving a problem. As far as cancer is concerned, we are definitely not there yet. But are we on the right track in the first place?
Veteran scientist Paul Davies and his team tried to look at the problem from a different perspective – as having an evolutionary root at “the dawn of multicellularity”. Stated simply, they posit a model wherein cancer is caused by reactivation of ancient ‘vestigial’ genes that promoted proliferation of cells more than 600 million years ago when early multicellular organisms existed as tumour-like colonies of cells2. Multicellularity of the present kind where cell groups (tissues) are differentiated to perform specialized tasks had not evolved then. Their outside-the-box atavistic model points to an extremely deep trait of living beings of rising from the dead. I have witnessed such risings in the sprouts of eucalypts growing on trees decimated by the 2020 bushfires here in Australia. The strategy for cancer treatment, therefore, should target the conditions that trigger reactivation of these ancient genes, suggest Davies and colleagues3.
Eucalyptus sprouts on burnt tree
One such strategy is to expose the affected area with elevated oxygen levels. The idea stems from the fact that prior to extensive cell specialization, conditions on the earth were that of less oxygen. The cells used a different energy generation strategy then that relies on a mechanism called fermentation. The dominant energy generation mechanism in our cells uses oxygen to make more energy units via cellular respiration. Mind you, our cells also possess the provision of fermentation process. Cancer cells are known to downregulate cellular respiration in preference to this primitive mechanism of fermentation, a condition known to cancer specialists as Warburg effect. The idea of treatment with elevated oxygen levels is therefore an effort to eliminate the condition of less oxygen (hypoxia) in the vicinity of cancer cells which could have triggered reactivation of ancient gene and hence fermentation in these cells. The low oxygen environment of tumours is caused by high rate of proliferation of cancer cells which cannot have access to enough oxygen because of low rate of formation of new blood vessels for supply4.
Some researches ascribe the switch from cellular respiration to fermentation in cancer cells to malfunction in mitochondria, the organelle where respiration is carried out. The problem with such a conclusion is that Warburg effect is also detected in cancer cells with healthy mitochondria5. Mitochondrial functions, including energy generation, are now considered necessary for tumour formation and proliferation4. Not only that, some tumorigenic cells are found to depend on cellular respiration and, surprisingly, have defective fermentation line of energy generation6. Such cancer stem cells differ from other cancer cells in that they are also multidrug resistant.
Drug resistance is a major obstacle in cancer treatment and a cause of many cancer deaths. The most common cancer treatment of chemotherapy actually uses an inbuilt capacity of cells to self-destruct. The cell has a preprogrammed mechanism of demolishing itself without causing damage to adjacent cells. Programmed cell death occurs when mitochondria indicate to the cell that they are under environmental stress. Chemotherapy aims at signalling mitochondria to activate the death processes in cancer cells7. Such signalling works because cancer cells do not have their death machinery disabled. Cancer only causes cells to regulate some of their proteins that help with not initiating the death machinery and hence cancer cells continue to proliferate. In many cases, cancer cells gradually become resistant to chemotherapeutic agents during the course of treatment. Such resistance is allegedly caused by subdued response of mitochondria to the effects of agents8. What causes mitochondria to change their response is an intriguing unknown.
The pathways of fermentation and cellular respiration are connected in normal cells via an intermediate compound called pyruvate. Pyruvate forms outside of mitochondria from glucose and is carried inside mitochondria for further energy generation via respiration. Pyruvate is escorted into the mitochondria by a carrier complex. Intriguingly, in colorectal cancers, these carriers are found to be less in number. Thus the link between glucose metabolism outside of and inside mitochondria is broken in cancer. It has been further found that in such cases, fatty acid uptake from outside into mitochondria increases. Note that mitochondria can carry its functions via fatty acid metabolism in addition to pyruvate metabolism. With pyruvate pathway blocked because of loss of carriers, it relies for its functions on fatty acid pathway in cancers. This feature of break in pyruvate import into mitochondria is considered necessary and sufficient condition for cancer initiation9.
Normal (blue) and cancer (red) cell energy generation
Another feature of cancer that arouses curiosity is its uncanny resemblance to certain aspects of sex. One such aspect is that cancer cells frequently express genes that are normally exclusively expressed in testis10. Expression of such genes that are related to the sexual cell division (meiosis) and to germ cells in general has led to a notion that cancer development might represent transition from somatic to germline behaviour11, 12.
During normal cell division (mitosis), there is an important stage called G1/S checkpoint where the key decision whether to proceed with cell division or not is made. The decision is made after taking stock of availability of nutrients and enzymes required for the process. This important checkpoint is inactivated in some special cases, such as in primordial germ cells in mice before sex determination13 and in induced pluripotent stem cell (iPSC)14. The checkpoint is also found to be inactive in a majority of cancer cases15. At this juncture, I remind myself of the role mitochondria play during G1/S checkpoint. A study has found that mitochondria form an unusually hyperpolarized giant tubular network at the G1-S transition16. This hints at mitochondria controlling G1/S checkpoint which has been found to be the case in the fly Drosophila17. What happens to mitochondria during this stage in cancer cells, I ask myself.
As with most cellular processes, mitochondria appear to be deeply involved in cancer too. Is the mitochondrial DNA (mtDNA) in cancer cells any different from normal cells? I searched and found that tumour cells usually have fewer mtDNA copies than normal cells18. Further, mtDNA fragments are found to be inserted into the nucleus in cancer cells during the lifetime of patients and this could have had causative influence in cancer development19. A rather interesting side note here is that in yeast such mitochondrial insertions have been found to promote replication of nuclear DNA20. Also important in cancer development are mutations of mtDNA that exist in many cancers21, most notably in the control region of mtDNA but also of genes responsible for enzymes required for biosynthesis.
Meanwhile, support for the atavistic model of cancer is increasing by the day. Analysis of data from the Cancer Genome Atlas has shown that, in several cancer types, genes identified typically with unicellular organisms were upregulated and those belonging to multicellular organisms were inactivated22 indicating that cancer is driven by reactivation of ancient gene regulatory networks. Also supporting the atavistic model is a proposition that tumour growth represents an in-between mechanism of reproduction that utilises certain features of meiosis to reinstate tumour germline which manifests itself as altered chromosomes which is a hallmark of cancer23.
What to make of all this? I cannot overlook the pointers which tell me that we need to continue to have a closer look at mitochondria and its DNA, more than that of the cell itself. Cancer defies cell’s preprogrammed limit of 40-60 replications (Hayflick limit) by manipulating the limit enforcing structure (telomere). The focus naturally is therefore on the cell’s DNA. One study24 has even held random “bad luck” mutations of DNA mainly responsible for cancer over other factors such as environment and heredity. Such mutations, the study concludes, are caused by DNA replications and are responsible for variance of cancer risk among various organs. The root cause however must be a level deeper I believe. I think of my review article25 which takes a holistic view of mutations of mtDNA at various levels of containment. Mitochondria maintains its health and keeps mtDNA mutations in check by a fusion-fission dynamism where it destroys mitochondrial fragments carrying more mutation via a process known as mitophagy. Does mitophagy have any bearing on cancer? There indeed is a connection. More on that later.
- Raza, A. (2019). The First Cell: And the Human Costs of Pursuing Cancer to the Last. Basic Books.
- Davies PC, Lineweaver CH. Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors. Phys Biol. 2011 Feb;8(1):015001. doi: 10.1088/1478-3975/8/1/015001.
- Lineweaver, C. H., Davies, P. C., & Vincent, M. D. (2014). Targeting cancer’s weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model.BioEssays, 36(9), 827-835.
- DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2(5):e1600200.
- Liberti MV, Locasale JW. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem Sci. 2016 Mar;41(3):211-218.
- Viale, Corti and Draetta (2015) Tumors and mitochondrial respiration: a neglected connection. Cancer Research 75(18).
- Sarosiek KA, Ni Chonghaile T, Letai A (2013) Mitochondria: gatekeepers of response to chemotherapy. Trends Cell Biol23:612-619
- Coku, J., Booth, D. M., Skoda, J., Pedrotty, M. C., Vogel, J., Liu, K., … & Hogarty, M. D. (2022). Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance.The EMBO Journal, 41(8), e108272.
- Bensard, C. L., Wisidagama, D. R., Olson, K. A., Berg, J. A., Krah, N. M., Schell, J. C., … & Rutter, J. (2020). Regulation of tumor initiation by the mitochondrial pyruvate carrier. Cell metabolism, 31(2), 284-300.
- Bruggeman, J. W., Koster, J., Lodder, P., Repping, S., & Hamer, G. (2018). Massive expression of germ cell-specific genes is a hallmark of cancer and a potential target for novel treatment development. Oncogene, 37(42), 5694-5700.
- Feichtinger, J., Larcombe, L., McFarlane, R.J. (2014) Meta-analysis of expression of l(3)mbt tumor-associated germline genes supports the model that a soma-to-germline transition is a hallmark of human cancers. International journal of cancer. 134(10):2359-65.
- McFarlane, R. J., & Wakeman, J. A. (2017). Meiosis-like Functions in Oncogenesis: A New View of Cancer. Cancer research, 77(21), 5712-5716.
- Bloom JC, Schimenti JC. Sexually dimorphic DNA damage responses and mutation avoidance in the mouse germline. Genes Dev. 2020 Dec 1;34(23-24):1637-1649. doi: 10.1101/gad.341602.120.
- Araki, R., Hoki, Y., Suga, T. et al. Genetic aberrations in iPSCs are introduced by a transient G1/S cell cycle checkpoint deficiency. Nat Commun 11, 197 (2020).
- Molinari M. Cell cycle checkpoints and their inactivation in human cancer. Cell Prolif. 2000 Oct;33(5):261-74.
- Mitra K, Wunder C, Roysam B, Lin G, Lippincott-Schwartz J (2009) A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase. Proc Natl Acad Sci USA 106:11960-11965.
- Mandal S, Guptan P, Owusu-Ansah E, Banerjee U (2005) Mitochondrial regulation of cell cycle progression during development as revealed by the tenured mutation in Drosophila. Dev Cell 9:843-854.
- Reznik E, Miller ML, ?enbabao?lu Y, Riaz N, Sarungbam J, Tickoo SK, Al-Ahmadie HA, Lee W, Seshan VE, Hakimi AA, Sander C. Mitochondrial DNA copy number variation across human cancers. Elife. 2016 Feb 22;5:e10769.
- Puertas, M. J., & Gonzalez-Sanchez, M. (2020). Insertions of mitochondrial DNA into the nucleus: effects and role in cell evolution. Genome, 63(8), 365-374.
- Chatre, L., & Ricchetti, M. (2011). Nuclear mitochondrial DNA activates replication in Saccharomyces cerevisiae. PLoS One, 6(3), e17235.
- Wallace, D. C. (2012). Mitochondria and cancer. Nature Reviews Cancer, 12(10), 685-698.
- Trigos AS, Pearson RB, Papenfuss AT, Goode DL (2017) Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors. Proc Natl Acad Sci USA 114:6406-6411.
- Salmina, K., Huna, A., Kalejs, M., Pjanova, D., Scherthan, H., Cragg, M. S., & Erenpreisa, J. (2019). The cancer aneuploidy paradox: In the light of evolution. Genes, 10(2), 83.
- Tomasetti, C., & Vogelstein, B. (2015). Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science, 347(6217), 78-81.
- Deonath, A. (2021). Evolution of eukaryotes as a story of survival and growth of mitochondrial DNA over two billion years. Biosystems, 206, 104426.