Can cancer cells really be starved to death?

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Can cancer cells really be starved to death?

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Can cancer cells really be starved to death? Nature : Princeton researchers found that tumor metabolism is slower than expected!

Why can tumor cells expand crazily and rapidly?
Is it because the metabolism is different from normal cells?

As early as 1925, scientist Otto Heinrich Warburg discovered that most tumor cells rely on aerobic glycolysis to supply energy for their own metabolism (Warburg effect), while normally differentiated cells mainly rely on mitochondrial oxidative phosphorylation (TCA cycle) or anaerobic Glycolysis provides energy for cells.

However, how much energy cancerous tumor cells consume to grow in mammals has long puzzled scientists. They hypothesize that tumors are energy-hungry and can rapidly metabolize nutrients, putting healthy tissues such as the heart, liver, and pancreas at a disadvantage in metabolizing nutrients.

But in a new study published in Nature , Joshua Rabinowitz’s research team from Princeton Chemistry and the Ludwig Princeton Branch has demonstrated for the first time that the opposite is true: Tumors convert nutrients into usable substances. The process of harnessing cellular energy is very slow. This slowdown may help tumors conserve energy to complete tasks such as proliferation and spread in a wider range [1] .

Using isotopic tracer infusion, mass spectrometry (MS), and quantitative modeling of the resulting metabolite labeling data, they developed and validated a strategy to measure TCA cycle flux in mouse tissues and tumors. Glucose usage flux was also quantified using 2-deoxyglucose infusion.

The above methods demonstrate that tissues from healthy mice generate at least 90% of their ATP using the TCA cycle and oxidative phosphorylation. However, primary solid tumors show obvious inhibitory effect on TCA, but still produce most of ATP through oxidation, indicating that the total ATP production rate of solid tumors is much lower than that of healthy organs .

Inhibition of the TCA cycle in primary solid tumors. TCA cycle is highly active in metastatic tumors

First, the researchers established a systems-level map of tissue energy metabolism in mice.

Based on the definition that metabolic flux is equal to the turnover rate of a molecule through a metabolic pathway, TCA flux is the product of the initial rate at which the labeled fraction rises upon introduction of a labeled substrate and the sum of metabolites in the TCA pathway.

So, which metabolite should be selected for labeling? In different tissues, lactate is the main fuel of the TCA cycle and can enter tissues rapidly.

Thus, the rate at which TCA metabolites are labeled can reflect TCA flux by intravenously injecting [U-13C]-labeled lactate in mice and measuring them at different time points.

Legend: TCA flux measurement method flow chart【1】

The researchers applied TCA flux measurements to several cancer models in mice and found that tumors had lower TCA fluxes than healthy tissue.

In five primary solid tumor models, TCA flux measured by injection of [U-13C]lactate or [U-13C]glutamine was lower than that of almost all healthy tissues.

For example, TCA flux was 6-fold slower than in healthy pancreas both in a genetically modified mouse (Kras mutant and Trp53 deficient) pancreatic tumor model (GEMM PDAC) and in a subcutaneously implanted pancreatic tumor mouse model (Flank PDAC).

Similar results were also observed in lung cancer model and colon cancer model. In contrast to the low TCA flux in solid tumors, a transplantable mouse model of NOTCH1-driven T-cell acute lymphoblastic leukemia showed approximately 3-fold higher TCA flux compared with healthy mouse spleen.

Thus, primary solid tumors in mice but not leukemia have lower TCA flux compared to healthy tissue. This result is consistent with the Warburg effect.

Legend: Comparison of TCA flux in healthy mouse tissues and mouse models of pancreatic cancer, lung cancer, colon cancer and T-cell acute lymphoblastic leukemia 【1】

What about TCA flux in metastases? Tumor metastasis requires cancer cells to migrate out of the tissue, survive in the blood or lymph, and establish a new tissue niche.

Previous studies have shown that metastatic cancer cells have elevated levels of reactive oxygen species (ROS), which may arise from the electron transport chain. To measure TCA flux in metastatic tumors in mice, the researchers performed experiments using two orthotopic breast cancer xenograft mouse models that metastasized to the lung.

They found that in both models, metastatically colonized lungs had higher TCA fluxes compared with primary tumors and surrounding healthy lung tissue.

Legend: Lung metastases have higher TCA flux than primary tumors 【1】

Tumor production is slow

Although solid tumors have lower TCA fluxes than healthy tissues, they may compensate through high levels of glycolysis to achieve high production levels.

To precisely measure cellular glucose flux, the researchers injected mice with [1-13C]-labeled 2-deoxyglucose. 2-Deoxyglucose can be taken up into cells by glucose transporters and phosphorylated, but cannot be further metabolized.

Using data on glucose flux and TCA flux, the researchers calculated the overall rate of ATP synthesis.

They found that in solid tumor models of pancreatic, lung and colon cancer, primary solid tumors in mice produced ATP more slowly than corresponding healthy tissues. Further research found that tumors obtained a higher proportion of ATP from glycolysis than healthy tissue.

But despite this, most ATP is produced through oxidation in every tissue and tumor type.

Thus, solid tumors in mice produce and use ATP more slowly than most healthy tissues, contrary to the notion that tumors are generally hypermetabolic.

However, this approach cannot distinguish whether tumors have slow ATP production due to low metabolic demand or low ATP production capacity (for example, due to limited nutrient availability).

Legend: Tumors synthesize ATP faster than healthy tissues 【1】

How do tumors expand while utilizing less ATP? The researchers further investigated pathways primarily functional in ATP consumption, including enzyme secretion and fat digestion in the pancreas, bicarbonate and sodium recycling in the kidney, and gluconeogenesis and glycogen metabolism in the liver.

They found that gene expression in these pathways was significantly downregulated in tumors compared with healthy tissue.

In the liver and kidney, lower expression of these genes may result in the encoded enzymes and ion pumps consuming less ATP; whereas in the pancreas, ATP sparing occurs through reduced synthesis of exocrine enzymes.

These data suggest that solid tumors downregulate tissue-specific ATP-consuming functions, thereby sparing ATP consumption to support proliferation .

Legend: Tumors down-regulate ATP-consuming tissue activities 【1】

Taken together, in five different types of cancer, the team found that tumors proliferate successfully on low energy budgets , in part because they ignore the normal tissue functions that healthy organs perform for the benefit of the whole body. “Tumors are facing a harsh metabolic environment, and they don’t have the vasculature that would allow the rest of the body to develop. So they’re forced to make do with less,” Rabinowitz said.

This finding has major implications for anti-cancer strategies because it directs our attention to slowing down energy metabolism.

Some proposed treatments for cancer patients revolve around the ” starvation therapy ” ” starve the tumor ” strategy, assuming that tumors cannot grow without nutrients, which now seems questionable.

Because with the progress of solid tumors, the uncontrolled growth of cancer cells can still be promoted under the condition of limited ATP energy generation.

references:
【1】 Bartman, CR, Weilandt, DR, Shen, Y. et al. Slow TCA flux and ATP production in primary solid tumors but not metastases. Nature (2023). https://doi.org/10.1038/s41586-022 -05661-6

Can cancer cells really be starved to death?

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