Being old and not dying is a thief!

Zi said: "To be old and not to die is to be a thief.
"
Although this sentence is sometimes taken out of context, for some people who are old and disrespectful, or even do evil because of their age, Singularity feels that this is really a curse.

And there are definitely not a few old and bad cells in the human body.

A recent study by a team at Kumamoto University in Japan showed that tumor-associated fibroblasts (CAFs) in the microenvironment of gastric cancer will become the driving force of gastric cancer peritoneal metastasis in the aging state.

Under the action of chronic inflammation, CAFs will enter the senescence-associated secretory phenotype (SASP) state.
By activating the JAK/STAT3 pathway, gastric cancer cells can promote the formation of metastases in the peritoneum.
Therefore, targeted cutting off of this pathway is expected to prevent the most serious gastric cancer.
One of the strong killer moves [1].

The research is published in Cell Reports.

The appearance of peritoneal metastasis often means that gastric cancer has entered the most advanced and dangerous stage, and the survival period of patients is generally only a few months [2].

Finding a way to cut off the peritoneal metastasis has become a key issue in the treatment of gastric cancer.

As the importance of the tumor microenvironment has been continuously revealed in recent years, scientists have also turned their attention to other cells in the gastric cancer microenvironment.

The pathogenesis of gastric cancer is mostly related to the chronic inflammation caused by Helicobacter pylori infection.
In the long-term inflammatory environment, the originally benign cells are likely to be infested.

In diffusely infiltrating gastric cancer (“leather stomach”) and malignant ascites of patients with peritoneal metastasis, the research team found CAFs that showed SASP status, and from the perspective of genes and cytokine phenotypes, these CAFs are exactly The tumor microenvironment from patients with gastric cancer is not native to the peritoneum.

The research team cultured CAFs isolated from samples of gastric cancer patients after surgery under in vitro conditions and found that under the combined action of the three inflammatory cytokines IL-1α, IL-1β and TNF-α, CAFs’ NF- The kB pathway will be activated and begin to enter a state of aging, which is the first step for them to deteriorate.

3CKs are three kinds of inflammatory cytokines As mentioned earlier, the occurrence of gastric cancer is related to chronic inflammation, so there are not too many three inflammatory cytokines in the microenvironment.

After epigenetic regulation, that is, the loss of H3K27me3 mediated by EZH2 down-regulation, CAFs will remain in the SASP state, and they will become accomplices to cancer cells.

Further experiments have shown that the activation of the JAK/STAT3 pathway of CAFs can help gastric cancer in more than one way.
The first is to secrete IL-6 and other cytokines to accelerate the proliferation of cancer cells, and the second is to secrete BCL-2.
Anti-apoptotic proteins such as anti-apoptotic proteins reduce the apoptosis of cancer cells in the peritoneal environment and help them form metastases.

Therefore, the treatment of CAFs can indirectly cut off the peritoneal metastasis pathway of gastric cancer cells.
The research team used the JAK2/STAT3 inhibitor under research, which effectively reduced the peritoneal metastasis of gastric cancer in the mouse model.

The above picture is a little more indirect, and the following direct cut is very intuitive.
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Associate Professor Shimoto Chongyin of Kumamoto University who presided over this study said that due to the high degree of malignancy of peritoneal metastasis and fewer treatments, the peritoneum can be blocked in advance by targeting CAFs.
Metastasis has a high clinical value.
His team also found that CAFs may also be involved in the resistance of gastric cancer cells to chemotherapy [3].

It can not only promote peritoneal metastasis, but also mediate chemotherapy resistance.
You bunch of aging CAFs are not a thing, right? If you don't let the patients get better, then sooner or later there will be treatments that won't let you get better.
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 References: 1.
Yasuda T, Koiwa M, Yonemura A, et al.
Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination[J].
Cell Reports, 2021, 34(8): 108779.
2.
Yarema R, Оhorchak М, Hyrya P, et al.
Gastric cancer with peritoneal metastases: Efficiency of standard treatment methods[J].
World Journal of Gastrointestinal Oncology, 2020, 12(5): 569.
3.
Uchihara T, Miyake K, Yonemura A, et al.
Extracellular vesicles from cancer-associated fibroblasts containing annexin A6 induces FAK-YAP activation by stabilizing β1 integrin, enhancing drug resistance[J].
Cancer Research, 2020, 80(16): 3222-3235.
Source: Dana -Farber Cancer Center Author of this article | Tan Shuo