Release date: 2017-08-08
Yesterday, we pushed an article saying that the risk of esophageal cancer in patients with periodontal disease increased by 228%. We received a lot of messages in the background, and some of the messages said: it is relevant and not useful.
Five months ago, we also pushed an article about periodontal disease as a risk factor for colorectal cancer and lymphoma. The background message also has a similar questioning voice.
For some people, the mouth and the intestines are too far apart, and it is difficult to get involved. For another part of the world, it seems that there can be any relationship between any two events in the world, so there is no need for mediocrity.
Recently, Professor Fang Jingyuan, Associate Professor Chen Wei, Associate Professor Hong Jie and Chen Haoyan from the Department of Gastroenterology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, and Professor Zou Weiping from the University of Michigan, USA, cooperated for the first time to demonstrate the mechanism of Fusobacterium nucleatum. Fusobacterium nucleatum can promote the tolerance of colorectal cancer to chemotherapy by regulating the autophagy of cancer cells. And Fusobacterium nucleatum is precisely the Gram-negative bacteria commonly found in our mouth. This important finding was published in the top journal Cell (1).
From left to right: Associate Professor Chen Wei, Professor Fang Jingyuan, Associate Researcher Hong Jie, Professor Zou Weiping, Associate Researcher Chen Haoyan
Intestinal cancer ranks third in all malignant tumors, and mortality ranks second (1), which is a major threat to human health. Chemotherapy is one of the commonly used anticancer therapies in the clinic. In particular, surgery and chemotherapy are the most common treatment options for patients with advanced colorectal cancer (2). However, although chemotherapy has shown good results in the early stages of treatment, patients eventually develop chemotherapy resistance and cause cancer recurrence. Therefore, the 5-year survival rate of patients with advanced colorectal cancer is only about 10% (3).
At the same time, although immunological checkpoint inhibitors have been effective in treating a variety of advanced cancers in recent years. However, unfortunately, the vast majority of colorectal cancer (CRC) is not sensitive to immunotherapy. Only a small percentage of CRC patients with mismatch repair defects can benefit from immunotherapy (4). Therefore, in order to improve the survival of patients with advanced CRC, it is necessary to understand the mechanism of CRC patients' resistance to chemotherapy.
In recent years, a series of studies have found that intestinal microbes can not only affect the effects of chemotherapy and immunotherapy by regulating local immune responses (5), but also closely related to the formation and metastasis of CRC. For example, in 2011 scientists discovered the presence of Fusobacterium nucleatum in the intestines. In 2012, it was found that the content of Fusobacterium nucleatum gradually increased during the development of CRC (6). Last year, scientists also found that Fusobacterium nucleatum is also closely related to the survival of patients with CRC, the higher the content, the shorter the patient's survival (7).
At this point, Fusobacterium nucleatum has aroused great interest. Researchers began to try to understand the drug resistance and recurrence of intestinal cancer from the perspective of Fusobacterium nucleatum. The room professor is a member of this team.
To explore the relationship between Fusobacterium nucleatum and chemoresistance of intestinal cancer. The team of professors recruited a large number of CRC patients (including cancer recurrence and non-recurrence patients) and systematically analyzed their tumor tissues. They found that the content of Fusarium nucleatum in tumor tissues of patients with CRC recurrence was significantly higher than that of CRC. Recurring patients. Moreover, the higher the content of Fusobacterium nucleatum in the tumor tissue of CRC patients, the worse the prognosis of patients is often worse.
Fusobacterium nucleatum
The researchers used the method of gradually increasing the concentration of chemotherapeutic drugs to obtain resistant SW480 cells (a CRC cell that is sensitive to chemotherapy). Then, the SW480 cells, the resistant SW480 cells, and the SW480 cells cultured with Fusobacterium nucleatum were separately treated with chemical drugs. They found that SW480 cells cultured with Fusobacterium nucleatum were as resistant to chemotherapy-resistant SW480 cells. In other words, Fusobacterium nucleatum in the human intestine does induce CRC cells to be resistant to chemotherapy.
So how does Fusarium nucleatum induce chemotherapy resistance? To this end, the researchers cultured CRC cells with Fusobacterium nucleatum, followed by transcriptome analysis of common CRC cells and CRC cells cultured with Fusobacterium nucleatum. It was found that among colon cancer cells cultured with Fusobacterium nucleatum, 992 genes were down-regulated and 1466 genes were up-regulated.
Thereafter, by single-sample gene enrichment analysis, Western blot analysis, and transmission electron microscopy, it was found that autophagy signals were significantly activated in colon cancer cells co-cultured with Fusobacterium nucleatum. Previous studies have found that autophagy pathways are associated with chemoresistance (9), which means that Fusobacterium nucleatum may cause resistance to chemotherapy by causing autophagy in CRC cells.
To test this, the researchers cultured Fusobacterium nucleatum with CRC cells and then added chemotherapy drugs and autophagy inhibitors. Chemotherapy resistance induced by Fusobacterium nucleatum was found to be counteracted by autophagy inhibitors. The researchers then identified relevant autophagy proteins, ULK1 and ATG7, involved in this process. It is indicated that the resistance to chemotherapy by Fusobacterium nucleatum is indeed achieved by activating the autophagy pathway.
However, during the course of the experiment, the researchers found a strange phenomenon, the increase in autophagy-related proteins was not caused by the corresponding increase in gene expression. This means that there is post-transcriptional regulation involved in the activation of autophagy signals.
This reminds the research team of miRNAs, which are common post-transcriptional regulatory elements in cells that play a regulatory role by degrading the corresponding mRNA or inhibiting its translation (10). Therefore, the researchers suspect that the increase in autophagy-associated proteins induced by Fusobacterium nucleatum may be associated with a corresponding decrease in miRNA content.
They found a high abundance of Fusobacterium nucleatum by performing a comprehensive miRNA expression analysis on six tumor tissues containing a large number of CRC patients with Fusobacterium nucleatum and six tumor tissues containing only a small number of CRC patients with Fusobacterium nucleatum. 68 of the CRC patients had decreased miRNA levels in cancer cells.
Subsequently, the researchers determined that the two miRNAs named miR-4802 and miR-18a* were involved in the activation of autophagy by comparing these 68 miRNAs with standard autophagy-associated miRNAs in the database, as well as real-time PCR. These two miRNAs can counteract the increase in autophagy-associated proteins induced by Fusobacterium nucleatum by inhibiting the synthesis of ULK1, ATG7.
And in the CRC mouse model, the researchers also demonstrated that autophagy inhibitors and the two miRNA analogs can inhibit chemoresistance induced by Fusobacterium nucleatum. All of these indicate that activation of autophagy by Fusobacterium nucleatum is achieved by selectively reducing the levels of these two miRNAs.
Finally, the researchers identified specific pathways for chemokine resistance mediated by Fusobacterium nucleatum, TLR4 and MYD88 innate immune signaling pathways. And in a mouse experiment, they found that inhibition of these two pathways can reverse the reduction of two miRNAs induced by Fusobacterium nucleatum, the increase in autophagy-associated proteins, and chemoresistance.
Specific mechanism of Fusarium nucleatum mediated chemotherapy resistance
Overall, in this trial, the researchers demonstrated that C. nucleatum-mediated chemoresistance is caused by a selective reduction of miR-4802 and miR-18a* by acting on TLR4 and the MYD88 pathway, which in turn activates Caused by phagocytosis.
Here, I still want to talk about our article yesterday. After discovering the relationship between periodontal disease and esophageal cancer, Professor Jean Wactawski-Wende, Dean of the School of Public Health at the State University of New York, said, “The esophagus is close to the mouth, so periodontal pathogens may be more likely to acquire and infect the esophageal mucosa and promote this. The risk of cancer at the site."
For this study, is the study of periodontal disease a high risk factor for colorectal cancer and lymphoma, and does it suggest something? What is the relationship between the intestinal bacterium of our intestines and the oral cavity? This is really worth thinking about.
Most importantly, this discovery has enormous clinical value. If patients with intestinal cancer receive anti-H. rhizogenes or anti-autophagy treatment while receiving chemotherapy, it may have the effect of enhancing chemotherapy. Although clinical techniques for the targeted removal of an enteric microbe have not yet emerged, in mid-June this year, Nature reported a heavy study, and Dr. Scott J. Hultgren, a professor of molecular microbiology at the University of Washington School of Medicine, utilized mannoside Successfully and specifically clears E. coli in the intestine without disturbing the balance of the intestinal flora, and there is no problem of causing drug resistance (11).
Reference material
1.Yu TC, Guo F, Yu Y, et al. Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy [J]. Cell, 2017, 170(3): 548-563. e16.
2. Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016[J]. CA: a cancer journal for clinicians, 2016, 66(4): 271-289.
3.Dahan, L., Sadok, A., Formento, JL, Seitz, JF, and Kovacic, H. (2009). Modulation of cellular redox state underlies antagonism between oxaliplatin and cetuximab in human colorectal cancer cell lines. Br. J Pharmacol. 158, 610–620.
4. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency [J]. New England Journal of Medicine, 2015, 372(26): 2509-2520.
5.Zitvogel, L., Galluzzi, L., Viaud, S., Ve? tizou, M., Daille`re, R., Merad, M., and Kroemer, G. (2015). Cancer and the gut microbiota : an unexpected link. Sci. Transl. Med. 7, 271ps1.
6.Castellarin, M., Warren, RL, Freeman, JD, Dreolini, L., Krzywinski, M., Strauss, J., Barnes, R., Watson, P., Allen-Vercoe, E., Moore, RA , and Holt, RA (2012). Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 22, 299–306.
7.Mima, K., Nishihara, R., Qian, ZR, Cao, Y., Sukawa, Y., Nowak, JA, Yang, J., Dou, R., Masugi, Y., Song, M., Et al. (2016). Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut 65, 1973–1980.
8.Song, J., Qu, Z., Guo, X., Zhao, Q., Zhao, X., Gao, L., Sun, K., Shen, F., Wu, M., and Wei, L. (2009). Hypoxia-induced autophagy contributes to the chemoresistance of hepatocellular carcinoma cells. Autophagy 5, 1131–1144.
9. Bartel, DP (2009). MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233.
10. Gur C, Ibrahim Y, Isaacson B, et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack [J]. Immunity, 2015, 42(2): 344-355.
11.Spaulding CN, Klein RD, Ruer S, et al. Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist[J]. Nature, 2017.
Source: Singularity Network (micro signal geekheal_com)
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