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The Evolution of Cancer: How Ancient Pathways Fuel Modern Disease

Writer's picture: S AS A

Updated: Dec 9, 2024

Cancer remains one of the most feared diseases globally, with alarming statistics highlighting its widespread prevalence. According to current data, one in three women and one in two men will face a cancer diagnosis during their lifetime. While cancer research has made significant strides, a comprehensive understanding of its root causes remains elusive.


While its roots lie in genetic mutations and complex physiological processes, emerging evidence highlights the significant role that everyday choices—such as diet and lifestyle—play in its development and progression.


In this article, we delve into the fundamental question: What is cancer? We explore its intricate physiology, shedding light on the mechanisms that allow abnormal cells to evade the body's defenses and thrive. Furthermore, we examine how modern lifestyle factors, including dietary habits and physical activity, influence these processes, either promoting or mitigating the risk of cancer.


By understanding the connection between cancer’s biology and our daily choices, we can empower ourselves to make informed decisions that may reduce the risk of this devastating disease.


Global Cancer Statistics

  • Incidence and Mortality: In 2022, there were approximately 20 million new cancer cases and nearly 10 million cancer-related deaths worldwide. By 2040, these numbers are projected to rise to 29.9 million new cases and 15.3 million deaths​ (Comprehensive Cancer Information)

    .

  • Disparities: Cancer rates tend to be higher in countries with greater life expectancy and living standards. However, for cancers like cervical cancer, higher rates are seen in low-income regions​

    (Comprehensive Cancer Information)


Image Credit: DNAWeekly


What is Cancer?

At its core, cancer is a disease of uncontrolled cell growth. Normally, cells in the body grow, divide, and die in a regulated manner. This process is controlled by a delicate interplay of genetic signals, growth factors, and metabolic processes.


In cancer, these regulatory mechanisms fail. Mutations in a cell lead to unregulated growth and the cell's inability to undergo apoptosis, or programmed cell death. Over time, these abnormal cells form masses, or tumors, that can invade surrounding tissues and even spread to distant parts of the body—a process called metastasis.


Falling Back on Evolution’s Toolkit

Mitochondria, often referred to as the powerhouses of the cell, are responsible for producing energy efficiently through oxidative phosphorylation. When mitochondria are damaged (more on this in subsequent blogs), cells shift to a backup mode: fermentation. This process, though less efficient, does not rely on oxygen and was the primary energy-generating method in life forms that existed before oxygen became abundant on Earth. Unlike acute energy loss, which leads to immediate cell death, cancer cells experience chronic mitochondrial dysfunction. This gradual loss of energy production forces them to adapt by reactivating primitive metabolic pathways.


Cancer cells exploit this ancient pathway by metabolizing glucose and glutamine through fermentation, allowing them to survive and proliferate despite mitochondrial damage. This metabolic reprogramming is not a random mutation-driven process but a fallback strategy encoded in the evolutionary history of life.


Implications of the Evolutionary Link

Understanding cancer as a reversion to ancient energy production provides valuable insights:

  • Targeted Therapies: Since cancer cells depend on glucose and glutamine, restricting these fuels can inhibit their growth without harming healthy cells.

  • Therapeutic Precision: Therapies that exploit the metabolic differences between cancerous and normal cells may lead to treatments that are both more effective and less toxic.

  • Research Directions: Investigating how cells switch between metabolic pathways can reveal new ways to prevent or disrupt cancer progression.


By framing cancer as a metabolic response rooted in the distant past, we can appreciate how cancer is not a chaotic, genetic anomaly but a predictable metabolic shift that can be controlled. This perspective offers hope for more strategic interventions that align with the biology of both ancient and modern cells.



Image Credit: mattjarosy


Physiology of Cancer Cells

Cancer is a complex group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body (metastasis). Its development involves a series of physiological changes that disrupt normal cell functioning. Below, each primary cause of cancer is explained along with the role diet and lifestyle play in its onset or progression.


Cancer develops when cellular regulatory mechanisms fail, primarily due to disruptions in how cells control their growth, division, and death. Here’s how and why these failures occur:


1. Genetic Mutations

  • How: Cancer is often triggered by mutations in key genes responsible for regulating cell functions, such as oncogenes (which promote cell division) and tumor suppressor genes (which inhibit it).

  • Why: These mutations can occur due to DNA damage from environmental factors (e.g., smoking, UV radiation, diet and other lifestyle factors) or errors during cell replication. For instance, mutations in the TP53 gene, which encodes the p53 protein (a tumor suppressor), impair the cell’s ability to repair DNA or induce apoptosis (programmed cell death).


2. Loss of Apoptosis (Programmed Cell Death)

  • How: Normally, cells with significant DNA damage undergo apoptosis. In cancer, this mechanism is often disabled, allowing damaged cells to survive and proliferate.

  • Why: Mutations in apoptotic genes, such as BCL-2, can block this process. As a result, cells that should die continue dividing.


3. Uncontrolled Cell Proliferation

  • How: Cancer cells evade normal regulatory checkpoints in the cell cycle, allowing them to divide uncontrollably. Here's how:

    1. G1/S Checkpoint:

      • Ensures the cell is ready to replicate DNA.

      • Cancer cells bypass this checkpoint by overactivating growth signals (e.g., mutated Ras or PI3K pathways) or by silencing tumor suppressors like RB and p53.

    2. G2/M Checkpoint:

      • Verifies DNA is intact before mitosis.

      • Cancer cells override this checkpoint through defective DNA damage response mechanisms.

    3. Spindle Assembly Checkpoint:

      • Ensures proper chromosome alignment before division.

      • Cancer cells often tolerate chromosomal missegregation, leading to genomic instability.

    By bypassing these checkpoints, cancer cells avoid apoptosis (programmed cell death) and continue to proliferate despite DNA damage or other abnormalities. These dysregulations are driven by genetic mutations, epigenetic changes, and altered signaling pathways, contributing to tumor growth and resistance to therapies.

  • Why: Dysregulation often involves over-activation of growth signals (via mutated RAS oncogenes) and loss of growth inhibition (through inactivated RB or p21 proteins).


4. Metabolic Dysregulation (Warburg Effect)

  • How: Cancer cells undergo significant changes in how they generate energy. Unlike healthy cells, which primarily rely on oxygen-dependent processes in the mitochondria, cancer cells often switch to a less efficient but faster form of energy production called aerobic glycolysis, even in the presence of oxygen. This is known as the Warburg Effect. In addition to glucose, cancer cells increasingly depend on glutamine, an amino acid that serves as a vital fuel for both energy generation and biosynthesis. Glutamine supports the production of nucleotides, lipids, and other critical molecules required for rapid cell division and survival in nutrient-deprived environments.

  • Why: This shift allows cancer cells to rapidly consume glucose and use it to fuel both energy needs and the building blocks for new cells. This metabolic reprogramming supports rapid growth by providing intermediates for biosynthesis. Mutations in metabolic regulators, like MYC and HIF-1α, drive this shift. Glutamine's role goes beyond energy; it helps replenish intermediates in the tricarboxylic acid (TCA) cycle, supporting cell growth and redox balance. This metabolic reprogramming ensures that cancer cells can generate energy and essential building blocks even under stressful conditions.


5. Angiogenesis (New Blood Vessel Formation)

  • How: Tumors stimulate the formation of new blood vessels to secure a nutrient supply.

  • Why: They overexpress VEGF (vascular endothelial growth factor) to promote angiogenesis, which is normally tightly regulated.


6. Immune Evasion

  • How: Cancer cells evade detection and destruction by the immune system.

  • Why: They can downregulate antigens or upregulate immune checkpoint proteins like PD-L1, which suppress immune attacks.


7. Genomic Instability and Repair Defects

  • How: Defective DNA repair mechanisms allow the accumulation of mutations.

  • Why: Loss of function in genes like BRCA1/2, involved in DNA repair, leads to genomic instability, promoting cancer progression.


8. Epigenetic Changes

  • How: Cancer can arise not only from genetic mutations but also from epigenetic modifications (changes in DNA methylation or histone modification).

  • Why: These changes can silence tumor suppressor genes or activate oncogenes without altering the DNA sequence.


Image Credit: Researchgate


In summary, cancer emerges when multiple regulatory mechanisms that maintain cellular homeostasis fail. These failures result from a complex interplay of genetic mutations, metabolic shifts, immune evasion, and epigenetic changes. The combination of these factors allows cancer cells to proliferate uncontrollably, resist death, and spread throughout the body.


Rethinking Cancer: A Metabolic Perspective

Cancer has long been viewed as a genetic disease, driven by mutations that cause unchecked cell growth. However, emerging research challenges this narrative, suggesting a different root cause: dysfunctional energy metabolism. Building on the insights of Otto Warburg, who observed that cancer cells exhibit faulty respiration, favoring glycolysis even in oxygen-rich conditions—a phenomenon termed the Warburg effect. Despite his groundbreaking observations, Warburg's ideas were overshadowed by the rise of genetics and the allure of DNA damage theories.


Years later, there is revitalized interest in this metabolic anomaly. PET scans demonstrated that nearly all tumors exhibit impaired mitochondrial function and over expression of hexokinase 2 (HK2). Hexokinase 2 (HK2) plays a critical role in fuelling cancer cells by catalyzing the first step of glycolysis: the conversion of glucose to glucose-6-phosphate (G6P). HK2 is highly expressed in cancer cells compared to normal cells, providing an advantage in rapidly consuming glucose even under anaerobic conditions. Its presence hints at an evolutionary throwback to anaerobic environments, where energy-efficient glucose consumption was crucial for survival.

Feature

Hexokinase 1 (HK1)

Hexokinase 2 (HK2)

Expression

Ubiquitously expressed in normal tissues.

Predominantly expressed in cancer cells and embryonic tissues.

Regulation

Relatively stable and less regulated.

Upregulated by oncogenic pathways (e.g., PI3K-AKT) and hypoxia.

Mitochondrial Association

Minimal association with mitochondria.

Strong mitochondrial binding, directly accessing ATP and evading apoptosis by preventing cytochrome c release.

Role in Cancer

Limited role in cancer-specific metabolism.

Supports cancer proliferation by enhancing glycolysis and biosynthetic pathways.

Biosynthetic Intermediates

Produces glucose-6-phosphate, which supports basic cellular functions.

Produces intermediates like glucose-6-phosphate, 3-phosphoglycerate, and dihydroxyacetone phosphate for biosynthesis.

End Products of Biosynthesis

Basic energy and minor anabolic products.

- Nucleotides: Via ribose-5-phosphate from the pentose phosphate pathway.


 - Lipids: Dihydroxyacetone phosphate and acetyl-CoA for membrane formation.


 - Amino Acids: 3-phosphoglycerate for serine and glycine synthesis.


 - NADPH: Generated for anabolic reactions and redox balance.

Therapeutic Target

Limited utility as a cancer therapy target.

High potential due to its central role in metabolic reprogramming.

HK2's over expression and distinct role in metabolic reprogramming make it a critical target for anticancer therapies.This metabolic reprogramming underscores the adaptability of cancer cells and provides a promising target for therapeutic intervention.This metabolic shift is a hallmark of all cancers, not just a side effect.


Key Insights:

  1. Chronic Mitochondrial Dysfunction:

    • Environmental factors such as toxins, radiation, chronic stress, or prolonged oxidative damage impair mitochondrial function.

    • Dysfunction reduces oxidative phosphorylation efficiency, forcing cells to rely on fermentation (glycolysis) for energy, leading to an abnormal metabolic state.

  2. Inflammation:

    • Damaged mitochondria release reactive oxygen species (ROS) and other pro-inflammatory signals.

    • Persistent ROS production and mitochondrial distress activate inflammatory pathways (e.g., NF-κB, cytokine release), creating a pro-inflammatory microenvironment.

  3. Mutations:

    • Chronic inflammation damages nuclear and mitochondrial DNA through oxidative stress.

    • This damage disrupts cell cycle regulation, leading to genetic instability and accumulation of mutations that promote uncontrolled cell growth.

  4. Tumor Formation:

    • The combination of metabolic reprogramming and mutations enables clonal expansion of cancer cells.

    • Cancer cells adopt the Warburg effect, relying on glucose and glutamine fermentation to support biosynthesis and rapid proliferation.

  5. Metastasis:

    • Inflammatory signaling fosters an environment conducive to epithelial-mesenchymal transition (EMT), enabling cancer cells to invade surrounding tissues.

    • Mutations enhance the cancer cells' ability to evade immune surveillance, travel through the bloodstream, and colonize distant organs.



Why Aren’t We There Yet?

Despite compelling evidence, the metabolic theory of cancer faces resistance due to entrenched beliefs in the genetic model. For metabolic therapies to gain traction, medical schools must educate future physicians about cancer’s metabolic and evolutionary underpinnings. Further research and clinical trials are essential to validate the efficacy of the Press-Pulse approach (more on this in future blogs) and develop safe, targeted therapies.


Hope on the Horizon

By understanding the evolutionary underpinnings of cancer, it's physiology and studying the works of Dr. Warburg, Prof. Seyfried, Jason Fung etc offers a hopeful vision for the future of cancer treatment—one that focuses on metabolic control rather than genetic alteration. By understanding and exploiting cancer’s metabolic vulnerabilities, we can develop more effective, less toxic therapies that improve quality of life and survival rates.


The idea that cancer is “not as complicated as it’s made out to be” may sound bold, but it is grounded in years of meticulous research, going all the way back to 1920s. If we embrace this new framework, we could be on the cusp of a major breakthrough in cancer care.


As we move forward, we will delve deeper into the evolutionary premise behind cancer, drivers of gene mutations, and environmental factors that fuel cancer development and progression. By understanding these connections, we can further empower individuals to make informed choices and uncover potential strategies for prevention and management. Stay tuned as we explore the intricate links between metabolism and cancer in the next part of this series.



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