Abstract
Cancer is considered a genetic disease by the majority of modern scientists.
Nevertheless, evidence suggests that metabolic dysfunction lies behind cancer pathogenesis. This article aims to provide a clear picture of the mechanisms behind this disease by evaluating the supporting evidence.
Introduction
Cancer is a disease caused by the abnormal proliferation of cells leading to the formation of a malignant mass, called a tumor. A tumour can be either benign or malignant. The primary characteristic of a
malignant tumor compared to a benign one is its ability to metastasize. Metastasis is the process during which cells from the primary tumor break-off and travel to other parts of the body, where they proliferate.
There are different types of cancer depending on the original site of tumor manifestation. For example, breast cancer originates in the breast area, and can metastasize to other organs [1].
It appears that although our understanding of cancer has seemingly improved, cancer burden is on the rise.
More specifically, it is estimated that in 2050 the amount of new cancer cases will be 77% higher than in 2022 [2]. Cancer research should not only focus on elucidating disease mechanisms, but also ensure that these findings translate to improved clinical outcomes. This article aims to explore cancer pathogenesis and uncover whether the driver of the disease is genetic or metabolic.
Cancer as a Genetic Disorder – The Somatic Mutation Theory
Cancer is commonly perceived by the scientific community as a genetic disease. To what extent is this theory true and where did it originate? The gene theory of cancer originated in 1914 following Theodor Boveri’s suggestion that cancer is caused by abnormal chromosomal segregation during cell division.
Nevertheless, Boveri focused on developmental cytogenetics in model organisms and doesn’t appear to have directly experimented on cancer. Although Boveri focused on chromosomal instability behind mutagenesis, his observations were extended to somatic mutations, giving rise to the “somatic mutation theory” of cancer [3].
This theory is accepted by most modern scientists, although some argue that it should be reconsidered [4]. One of the first scientists to question the gene theory of cancer was C.D. Darlington. He proposed that cancer arises from mutations in cytoplasmic elements which he called “plasmagenes” [5].
Are somatic mutations the drivers of cellular tumorigenesis?
Although cancer cells do exhibit mutations, it is uncertain whether these are the drivers of the disease or merely the effect of uncontrolled proliferation. In order to investigate further whether nuclear elements are responsible for tumorigenesis, cytoplasmic/nuclear transfer experiments were conducted [6].
These revealed inconsistencies in the somatic mutation theory. More specifically, Israel et al. transferred cytoplasm from normal rat epithelial liver cells to tumorigenic cells and showed that tumorigenicity was suppressed in four out of five progeny clones, as summarized in Figure 1. This indicates that cytoplasmic elements have the ability to control tumor cell fate.
Moreover, Mintz et al. injected five teratocarcinoma cells derived from embryos into blastocysts and subsequently observed their development [7]. They concluded that carcinogenic cells exhibit developmental totipotency and have the ability to generate normally functioning adult tissues. These results, among others, indicate that acquiring tumorigenicity does not involve changes in genome structure but rather changes to tissue organization.
Evidence that supports the somatic mutation theory is mainly based around the concept of “driver mutations”. Driver mutations are defined by the National Cancer Institute as “changes in the DNA
sequence of genes that cause cells to become cancer cells and grow and spread in the body” [8]. Nevertheless, detecting driver mutations is a “notoriously difficult process” as reported by Brown et al. [9].
The process of detecting these mutations involves screening large populations of cancer cells for recurrent mutations as well as evaluating their mutability. Driver mutations have been associated with lower mutability rates compared to passenger mutations (considered to be a result of tumour hyperproliferation and genomic instability).
Figure 1: Summary of nuclear/cytoplasmic transfer experiments indicating that a tumour nucleus combined with normal cytoplasm can give rise to normal cells while a tumour cytoplasm with a normal nucleus can induce tumorigenicity. Figure by Jeffrey Ling and Thomas N. Seyfried [10].
The limitation introduced by this method is that there is lack of an objective gold standard and criteria to define a mutation as the driver [11]. In addition, genomic sequence studies have revealed
that there are over 60 million mutated genes expressed in different cancer cells, thus making the task of developing effective therapies a challenging one [12,13].
Moreover, although mutations can be common amongst cancer cells, there is not a single gene mutation that can be found in all cancer cells [12]. This highlights the increased variation between
tumour genomes and leads us to consider other pathogenic mechanisms.
Overall, although the somatic mutation theory is largely accepted, it is evident that it presents inconsistencies.
These urge us to delve deeper behind the notion that cytoplasmic/metabolic elements could be the drivers of cellular tumorigenesis [10].
Cancer as a Metabolic Disease
Otto Warburg was the first scientist to describe metabolic dysfunction in cancer cells and was awarded the Nobel prize for Physiology or Medicine in 1931 [14]. He described that cancer cells use anaerobic
glycolysis to generate energy even in conditions where oxygen was abundant [15].
He also hypothesized that this metabolic pathway is an adaptation of the cell to insufficient respiration [16]. The main pathway that is affected during lactate production is oxidative phosphorylation, which takes place in the mitochondria [17]. This indicates that during cancer pathogenesis dysfunctional
mitochondria can lead to impaired respiration and upregulation of the glycolytic pathway [10].
Anaerobic glycolysis is sustained through the production of oncometabolites: endogenous cellular metabolites that assist in tumor growth and proliferation [18].
These oncometabolites can also act as transcription factors, altering gene expression and inducing tumor formation [19].
The evidence mentioned above dictate that metabolic dysfunction precedes genetic instability by being the driver of altered gene expression itself.
Conclusion
Having in mind the aforementioned, it can be concluded that there is an abundance of evidence supporting that the mechanism of cancer pathogenesis involves metabolic dysfunction. This is characterized by mitochondrial dysfunction which involves increased oncometabolite production and the upregulation of anaerobic glycolysis.
Nevertheless, a combination of genetic and metabolic factors contributes to the growth
and metastasis of tumours. Therefore, future studies must focus on translating these findings into therapeutic approaches that consider lifestyle choices, which promote metabolic health.
References
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