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Cancer grows.

Cancer grows unchecked, unregulated, and with the ability to invade

Cellular Proliferation

Cancer cells grow and behave differently from normal cells, and these differences become more pronounced as a tumor's grade advances.

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Key Differences Between Cancer and Normal Cells

1. Uncontrolled Growth:

Normal cells are highly regulated, only proliferating when necessary and typically stopping when they have filled their space and function. In contrast, cancer cells bypass these regulatory mechanisms. They continue to grow and divide, ignoring the body's signals to stop. This uncontrolled growth is a hallmark of cancer. 

2. Avoidance of Apoptosis:

Normal cells undergo programmed cell death (apoptosis) when they are damaged or no longer needed. Cancer cells, however, can evade apoptosis, allowing them to survive and proliferate even when they are dysfunctional or form tumors.

 

3. Sustained Angiogenesis:

For tumors to grow beyond a certain size, they need a blood supply to provide oxygen and nutrients. Cancer cells can induce angiogenesis, the formation of new blood vessels, which normal cells do not typically do.

4. Ability to Invade and Metastasize:

Normal cells adhere to their own cell type in a specific location. Cancer cells can break this rule, invading neighboring tissues and spreading to distant sites in the body (metastasis).

Replication

During cellular replication, thymine, a key component of DNA, can be synthesized through two primary pathways: the de novo synthesis pathway and the salvage pathway. Both pathways are crucial for maintaining the nucleotide pools necessary for DNA replication and repair.

De Novo Synthesis Pathway

In the de novo synthesis pathway, thymine is produced from scratch using simpler molecules. This pathway is highly regulated and is critical during times of rapid cell division, where there is a high demand for DNA synthesis.

Salvage Pathway

The salvage pathway recycles thymidine from within the cell or from extracellular sources, conserving energy, and resources by not having to synthesize new nucleotides from scratch. Cancer, which has a dysregulated cell cycle, often uses the salvage pathway during replication which upregulates TK1.

Thymidine Kinase,
Type 1

Thymidine Kinase, type 1 (TK1) is a marker of dysregulated cellular proliferation.  Whereas, normal dividing cells primarily use de novo synthesis, cancer cells have a dysregulated cell cycle resulting in cell death and necrosis upregulating TK1.  This cytosolic enzyme leaks into circulation and is detected via a serum test.

TK1 was originally investigated in non-Hodgkins’s lymphoma, where TK1 concentrations can get very elevated. More recently, there are numerous publications showing TK1 to be a useful biomarker in LSA and solid tumors alike, both in humans and companion animals. TK1 studies show that it has clinical utility in cancer screening, cancer diagnosis, prognosis, and therapeutic effectiveness.

High grade tumors demonstrate rapid growth rates and a high propensity for necrosis due to their aggressive proliferation outpacing their blood supply. Further high grade tumors are more likely to invade surrounding tissues and metastasize to distant sites. High grade tumors . Studies have shown TK1 is directly associated with tumor grade, increasing proportionally as a function of both tumor grade and overall tumor burden.

Being a true proliferation marker, TK1 will rise and fall in relation to tumor activity. As cancer burden grows TK1 increases. With effective therapy, TK1 will decrease.

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Proliferation Rates and
Metabolic Pathways

The differences in key signaling pathways between high-growth (aggressive) and slow-growth (indolent) tumors significantly influence their biology, behavior, and response to treatment. These variations often depend on how certain cellular pathways are activated or suppressed.

Pathways that are more highly affected in high growth rate tumors include PI3K/Akt/mTOR, RAS/RAF/MEK/ERK, p53, Cell Cycle Regulators (e.g., Cyclin D, CDKs, and RB Pathway), and Hypoxia-Inducible Factor (HIF).

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High Growth Rate and Glycolysis

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  • High-grade, aggressive tumors often exhibit increased glycolytic activity. The rapid production of ATP and biosynthetic precursors supports their accelerated growth and proliferation needs.

  • This glycolytic shift is often driven by genetic alterations in cancer cells that enhance glucose uptake and fermentation, even in the presence of oxygen.

Slow Growth Rate and OxPhos

  • Low-grade, less aggressive tumors might rely more on OxPhos. These tumors are generally more differentiated and may retain some aspects of normal cellular metabolism.

  • A reliance on OxPhos can be linked to a lower rate of proliferation, where energy efficiency is more beneficial than the rapid energy turnover required by highly aggressive tumors.

Implications for
Cancer Therapy

Project-29 investigates how cancer proliferation and cancer metabolism can help to refine treatment

Understanding the metabolic preferences of tumors can guide therapeutic strategies:
  • Targeting glycolysis in high-growth, glycolytically active tumors with inhibitors of glycolytic enzymes (like hexokinase) or glucose transporters can be effective.

  • In contrast, targeting the mitochondrial function and OxPhos in tumors that rely more on oxidative metabolism might offer therapeutic benefits, particularly in tumors that are resistant to traditional therapies targeting glycolysis.

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The relationship between metabolic pathways and tumor growth rates highlights the complexity of cancer metabolism and its implications for tumor behavior and treatment. In veterinary oncology, as in human medicine, tailoring treatments to the metabolic profile of the tumor could enhance therapeutic efficacy and outcomes.

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