"Nature": Hypnotize tumor cells and inhibit tumor metastasis!

When introducing the latest research progress on tumors, Singularity Cakes often use an adjective: cunning.

 The word cunning is not an exaggeration to count the various discoveries in the process of tumor progression and metastasis.

They can mess up the immune cells and lose their anti-tumor ability.
They also plan ahead to spread the tumor cells at an early stage.
By the way, they can keep these cells in a dormant state.
Even if the primary focus is eliminated, they can also look for opportunities.
Wake up to establish metastases.

 So, I wonder if you have ever thought about a question: how do these tumor cells that have been spread dormant and wake up? This question was answered by researchers from the University of Basel in Switzerland in today's "Nature" magazine.

 They took the liver metastasis model of breast cancer as the research object and found that in the microenvironment where tumor cells are dormant, NK cells maintain tumor cell dormancy through interferon-γ signals, and activated hepatic stellate cells can secrete chemokines.
When NK cells are disabled, the dormant tumor cells will wake up [1].

 In other words, the interaction between NK cells and activated hepatic stellate cells is a key switch for regulating tumor cell dormancy.

Picture from veer.
com The unpredictable when dormant tumor cells wake up is like an untimely bomb, which has caused great distress to patients and researchers alike.

 In order to clarify this problem, in this study, the researchers used a mouse model of spontaneous breast cancer metastasis to conduct a study.

They found that there are different numbers of disseminated tumor cells in each tissue of the mouse, and the liver will preferentially dormant, basically in the form of single cells or small cell clusters (<10 cells).

 In tissue samples containing these dormant tumor cells, the expression of genes related to host immune defense and NK cell response increased.

Compared with normal metastases, the transcription levels of NK cell marker genes in these tissue samples were significantly higher.

 From this sign, the researchers thoroughly examined the immune cell populations in the liver and found that compared with livers without tumors, in livers containing dormant tumor cells, NK cells are the only change in both quantity and proportion.
Too many immune cells.

 Both classic NK cells and liver resident NK cells decrease during the process of metastasis formation, but only the latter increases slightly in the liver with dormant tumor cells.

In view of the observed series of differences, the researchers speculated that NK cells may play a decisive role in the dormancy and awakening of tumor cells.

 Sure enough, the use of antibodies to deplete NK cells will lead to the awakening and increase of dormant tumor cells in multiple organs, especially accelerating the formation of liver metastases, while the use of interleukin-15 (IL-15) to expand NK cell reserves greatly reduces the overall The burden of metastasis, and completely suppressed liver metastasis.

Comparison of survival time of mice treated with NK cell antibody (red), IL-15 and control group (IgG and PBS) how did NK cells do it? In liver samples of dormant tumor cells, NK cells have enhanced signaling pathways related to innate immunity and inflammation, including tumor necrosis factor and interferon-γ, which are prominent when NK cells are activated and are known to inhibit tumor cell growth.
Factor [2].

 Among these cytokines, molecules that respond to interferon-γ increased in dormant tumor cells.
Both in vitro simulation experiments and mouse experiments showed that the presence of interferon-γ significantly increased the proportion of dormant tumor cells.

This shows that NK cells use interferon-γ to keep tumor cells dormant.

 At this point, the question has been half answered.

So, what did NK cells go through to prevent them from being able to "hypnotize" tumor cells? By analyzing the transcriptome data of metastases, the researchers found that the transcription level of genes encoding activated hepatic stellate cells increased significantly.
Activated hepatic stellate cells (aHSC) are the main driver of liver fibrosis, and liver fibrosis Transformation is a typical precancerous lesion [3].

 The experimental results showed that the accumulation of aHSC specifically increased the liver metastasis of tumors, while the number of NK cells was severely decreased.

Even without dormant tumor cells, aHSC will destroy the immune response mediated by NK cells.

In both cases, the decrease in NK cells is due to the decrease in proliferation.

 It seems that aHSC can kill NK cells? Considering the importance of HSC-mediated paracrine signals in liver physiology and disease development [4], researchers speculate that aHSC may inhibit the proliferation of NK cells by secreting factors.

 Analysis of the secretory factor proteomics showed that the chemokine CXCL12 increased significantly, and there is a type of receptor CXCR4 on NK cells, which happens to be the receptor of CXCL12.
They determined that aHSC exerts its effect on NK cells through this pathway.
Inhibition.

a: NK cells maintain tumor cell dormancy through IL-15 b: aHSC inhibits NK cell proliferation through the CXCL12-CXCR4 axis, awakens tumor cells.
Analysis of biopsy samples of metastases and adjacent healthy liver tissues in breast cancer patients shows that aHSC is in A large number of metastases accumulate, which is negatively correlated with the level of NK cells, verifying the findings in the mouse model.

Analysis of gene expression data from published studies on liver metastases from colorectal cancer also showed the same correlation, indicating that this mechanism may not be limited to the type of primary tumor.

 Overall, this study reveals how NK cells keep disseminated tumor cells dormant, and how they lose control under the regulation of aHSC.

 However, the answers to some of these questions are still uncertain.
For example, in tissues with dormant tumor cells, the mechanism by which NK cells accumulate and trigger the production of interferon-γ; and the mechanism by which the CXCL12-CXCR4 axis wakes dormant tumor cells.
In how many types of tumors exist.

 Currently, drugs to inhibit CXCR4 are under development.
In the future, there may be other new therapies targeting NK cells.
Whether they can help maintain the hypnosis of NK cells on tumor cells and prolong the survival of patients is worthy of attention and discussion.
The problem.

 References: [1] Correia, AL, Guimaraes, JC, Auf der Maur, P.
et al.
Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy.
Nature (2021).
https://doi.
org/10.
1038/ s41586-021-03614-z[2] Barrow AD, Edeling MA, Trifonov V, et al.
Natural killer cells control tumor growth by sensing a growth factor[J].
Cell, 2018, 172(3): 534-548.
e19.
[3] Tsuchida T, Friedman S L.
Mechanisms of hepatic stellate cell activation[J].
Nature reviews Gastroenterology & hepatology, 2017, 14(7): 397.
[4] Taub R.
Liver regeneration: from myth to mechanism [J].
Nature reviews Molecular cell biology, 2004, 5(10): 836-847.
The author of this articleYing Yuyan