Sub-Journal of "Nature": Obesity will leak blood vessels and help cancer cells escape!

Let me start with a number-about 20% of deaths caused by cancer can be attributed to obesity [1].

This is not only due to the increased risk of a variety of cancers caused by obesity, the most terrible cancer metastasis will also increase the incidence of obesity.

In a retrospective cohort of nearly 20,000 early breast cancer patients, it was found that obesity at diagnosis was associated with a 46% increase in the risk of distant metastasis within 10 years and a 38% increase in the risk of death from breast cancer within 30 years [2 ].

Another small study also found that obesity is also related to the propensity for metastasis.
Patients with obese breast cancer are more likely to develop lung metastases and liver metastases, rather than brain metastases or bone metastases [3].

Why does obesity promote cancer metastasis? Recently, a study published in the journal "Nature Cancer" gave us part of the answer.

Researchers have found that obesity can cause neutrophil reprogramming, disrupt the adhesion of vascular endothelial cells, and increase the permeability of blood vessel walls.

In other words, obesity will cause blood vessels to leak into a sieve, and cancer cells will run away! [4] Source | veer.
com In order to clarify the effect of obesity on cancer, the researchers fed mice with a low-fat diet (LF) and a high-fat diet (HF).
10% of the energy in the former is provided by fat, and the latter Those are as high as 60%.

After 15 weeks of feeding, the mice on the high-fat diet gained a lot of weight.
At this time, the mice were injected with fluorescently labeled breast cancer cells through the tail vein.

48 hours after the injection, the researchers found that the breast cancer cells infiltrated into the lungs of the obese mice were 2.
3 times that of the control mice! The researchers also tried the same experiment in mice genetically causing obesity.

This kind of mice cannot control their appetite due to lack of leptin.

Similarly, compared with normal mice, the number of cancer cells infiltrated into the lungs of the genetically defective and obese mice was 3.
4 times.

This shows that obesity does promote the migration of cancer cells.

The migration of cancer cells in obese mice increases the infiltration of cancer cells into the lungs.
There are two main roles in this, one is the metastatic cancer cells themselves, and the other is the endothelial cells that act as a barrier to cancer metastasis.

The researchers cultured these cells with the serum of obese mice and found that the treated endothelial cells were significantly more conducive to cancer cell migration.

So what happened to the endothelial cells? The researchers performed RNA sequencing on endothelial cells and found that Foxo3 had the largest difference in transcription levels between obese and normal mice.

Previous studies have shown that FOXO3 can regulate the integrity of blood vessels [5], so researchers speculate that obesity is likely to change the permeability of blood vessels.

Sure enough, the diffusion of marker molecules in obese mice is stronger.

Moreover, the treatment of human microvascular endothelial cells and human umbilical vein endothelial cells with serum from obese mice also resulted in a decrease in barrier integrity and an increase in permeability.

All these indicate that obesity may promote the spread of cancer cells by increasing the permeability of blood vessels.

The experiment of increasing vascular permeability in obese mice is done here, and researchers feel that this phenomenon is a bit familiar.

When the body is exposed to pathogens, innate immune cells will loosen the connections between cells by regulating the expression of adhesion proteins to promote immune infiltration [6].
This is not a bit like it.

Sure enough, the researchers analyzed 10 proteins related to cell adhesion and found that in the lung tissue of obese mice, the expression of an adhesion protein called JAM1 was reduced by 59%.

Knockdown of JAM1 will increase the permeability of blood vessels.

The "behind the scenes" of decreased JAM1 expression is the neutrophils predicted by previous studies [7].

Obesity greatly reduces the expression of JAM1.
It turns out that obesity can lead to neutrophil reprogramming, and the expression of genes related to the production of reactive oxygen species (ROS) increases, while the expression of several genes related to antioxidant activity is down-regulated.

Further analysis showed that the production of ROS promoted the extracellular trap (NET) of neutrophils, resulting in increased vascular permeability and "leakage" of cancer cells.

Using antibodies to deplete neutrophils, use drugs to "anti-oxidize", or inhibit related peroxidase genes, can successfully reverse the "sieve blood vessels" of obese mice and reduce the escape of cancer cells.

Finally, the researchers also analyzed data from human patients.

Tissue specimens of lung metastases came from 22 patients with different primary tumors, and their BMI ranged from 19.
9 to 36.
3.

Cancer cells from patients with high BMI showed higher proliferative potential, and increased levels of oxidation and extracellular traps in neutrophils were observed.

The distribution of immune cells in the patient’s tissues never expected that the innate immune cells that were supposed to protect the human body were used by cancer cells here again.
I don’t know whether neutrophils are too stupid or cancer cells are too cunning.

In short, you must first settle the inside when you are getting rid of foreigners.
As for how to settle down, it depends on the follow-up research! References: [1] Calle, EE, Rodriguez, C.
, Walker-Turmond, K.
& Tun, MJ Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults.
N.
Engl.
J.
Med.
348, 1625–1638 (2003).
[2] Ewertz, M.
et al.
Efect of obesity on prognosis afer early-stage breast cancer.
J.
Clin.
Oncol.
29, 25–31 (2011).
[3] Osman , MA & Hennessy, BT Obesity correlation with metastases development and response to frst-line metastatic chemotherapy in breast cancer.
Clin.
Med.
Insights Oncol.
9, 105–112 (2015).
[4] https:// com/articles/s43018-021-00194-9[5] Potente, M.
et al.
Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization.
J.
Clin.
Invest.
115, 2382–2392 (2005).
[6] Weber, C.
, Fraemohs, L.
& Dejana, E.