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Author617 EditorEnzyme Beauty Globally, prostate cancer is the second leading cause of death in men after lung cancer.
It is often caused by excessive secretion of androgens
.
Therefore, for this disease, the most common clinical treatment is to reduce androgen levels through androgen deprivation therapy (ADT)
.
However, although the vast majority of patients initially respond to androgen deprivation therapy, most cases will eventually develop from hormone-sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC)
.
Previous studies have shown that the intestinal flora is closely related to the occurrence and development of cancer
.
However, the specific role of intestinal flora in the occurrence and development of prostate cancer is still unclear
.
So, what role does the intestinal flora play in the development of HSPC to CRPC? Is it possible for the intestinal flora to influence the progression of prostate cancer by synthesizing androgens? Recently, the Andrea Alimonti team of the Southern Swiss Oncology Institute (IOSI) published an article titled Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis in Science, which answered the above questions
.
Through a variety of mouse models and clinical samples, this article reveals for the first time that gut microbes can participate in the synthesis of androgens and can influence the development of prostate cancer in this way
.
First, the author used two mouse models of prostate cancer (TRAMP-C1 xenograft tumor model and Ptenpc–/-prostate knockout mice) to initially explore the relationship between the intestinal flora and the progression of CRPC
.
The author has castrated the mice (that is, surgical castration).
After castration, the mice will first enter the castration sensitive stage (CS), at which time the volume of the tumor decreases rapidly, and then enter the castration resistance stage (CR) , At this time the volume of the tumor gradually increases
.
However, what is interesting is that when a variety of broad-spectrum antibiotics are used to remove the intestinal flora of mice, the growth rate of tumors in the CR stage will be significantly slower, indicating that the intestinal flora will affect the progression of prostate cancer
.
In addition, the results have also been verified in the LNCaP xenograft mouse model and the patient-derived LuCaP35 xenograft mouse model
.
Further analysis of 16S rDNA sequencing revealed that the relative abundance of Ruminococcus gnavus and Bacteroides acidifaciens increased significantly in castrated mice in CR stage
.
Through the method of fecal bacteria transplantation (FMT), it was further found that the bacteria from the CR stage of mice and R.
gnavus can maintain tumor growth, while the bacteria from wild-type mice inhibit the development of CRPC
.
However, the analysis of the systemic and tumor-infiltrating immune cells of the mice after castration revealed that the changes in the intestinal flora did not have a significant impact on the systemic and local immune responses of the mice
.
So, how does the intestinal flora affect the development of tumors? Considering that the intestinal flora will affect the metabolism of the host, the author speculates that the intestinal flora may affect the metabolism of the host and regulate the progression of tumors.
Based on this, the author analyzed the serum metabolome of mice
.
It was found that in castrated mice treated with antibiotics, the concentration of androgen-dehydroepiandrosterone (DHEA) and testosterone decreased significantly
.
Therefore, the author speculates that the two microorganisms enriched in the CR stage-R.
gnavus and B.
acidifaciens may have the ability to synthesize androgens
.
In order to verify this conjecture, the author co-cultured these two kinds of microorganisms with a series of intermediate products of androgen synthesis pathways in vitro, and found that these two kinds of bacteria can metabolize pregnenolone and hydroxyprogesterone, and convert them It is a downstream metabolite including DHEA and testosterone
.
Then, the author further verified it in vivo
.
By injecting deuterium-labeled pregnenolone into castrated mice treated with or without antibiotics, it was found that the circulating concentrations of deuterium-labeled DHEA and testosterone in antibiotic-treated mice were significantly lower than those without antibiotics Treated mice
.
The above in vivo and in vitro results indicate that microorganisms enriched in the CR stage of mice can participate in the metabolism of androgens and maintain the growth of prostate tumors in this way
.
Finally, the authors performed verification in HSPC (n=19) and CRPC (n=55) patients
.
Through metagenomic testing of rectal swabs, it was found that many microorganisms from the genera Ruminococcus and Bacteroides were enriched in CRPC patients, and genes related to the biosynthetic pathway of steroid hormones were also significantly enriched in CRPC patients
.
Further analysis showed that Ruminococcus sp.
DSM_100440, Ruminococcus sp.
OM05_10BH, Streptococcus vestibularis and Clostridiales bacterium VE202_14 were associated with poor clinical outcomes, while Prevotella spp.
BCRC_81118, Marseille_P4119 and 885 were associated with better clinical outcomes
.
Among them, in vitro experiments show that Ruminococcus sp.
DSM_100440 can metabolize pregnenolone and hydroxyprogesterone into androgens such as DHEA and testosterone
.
Then, the authors used two patient-derived organoids—CP50 (sensitive to androgen deprivation) and CP50C (insensitive to androgen deprivation) to detect the effects of Ruminococcus sp.
DSM_100440 on the host
.
It was found that the bacteria only promoted the expression of androgen receptor target genes in CP50
.
Moreover, abiraterone, a selective inhibitor of CYP17A1, can inhibit the conversion of pregnenolone into DHEA and testosterone by microorganisms
.
In addition, in the mouse model, Ruminococcus sp.
DSM_100440 can also maintain tumor growth, further confirming that Ruminococcus sp.
DSM_100440 plays a certain role in tumor development
.
In summary, the study found that intestinal bacteria can promote the development of prostate cancer by synthesizing androgens
.
However, the study did not reveal the mechanism by which the intestinal flora induces changes in androgen levels, and the specific mechanism by which related intestinal bacteria synthesize androgens
.
The above-mentioned problems are worthy of our further research to provide more treatment methods for patients with prostate cancer
.
It is worth mentioning that in the same period, Science magazine also published a commentary on the study by Professors John A.
McCulloch and Giorgio Trinchieri, Gut bacteria enable prostate cancer growth
.
Original link: https:// Platemaker: Instructions for reprinting on the 11th [Original article] BioArt original article, personal forwarding and sharing are welcome, reprinting without permission is prohibited, all published The copyright of the work is owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
It is often caused by excessive secretion of androgens
.
Therefore, for this disease, the most common clinical treatment is to reduce androgen levels through androgen deprivation therapy (ADT)
.
However, although the vast majority of patients initially respond to androgen deprivation therapy, most cases will eventually develop from hormone-sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC)
.
Previous studies have shown that the intestinal flora is closely related to the occurrence and development of cancer
.
However, the specific role of intestinal flora in the occurrence and development of prostate cancer is still unclear
.
So, what role does the intestinal flora play in the development of HSPC to CRPC? Is it possible for the intestinal flora to influence the progression of prostate cancer by synthesizing androgens? Recently, the Andrea Alimonti team of the Southern Swiss Oncology Institute (IOSI) published an article titled Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis in Science, which answered the above questions
.
Through a variety of mouse models and clinical samples, this article reveals for the first time that gut microbes can participate in the synthesis of androgens and can influence the development of prostate cancer in this way
.
First, the author used two mouse models of prostate cancer (TRAMP-C1 xenograft tumor model and Ptenpc–/-prostate knockout mice) to initially explore the relationship between the intestinal flora and the progression of CRPC
.
The author has castrated the mice (that is, surgical castration).
After castration, the mice will first enter the castration sensitive stage (CS), at which time the volume of the tumor decreases rapidly, and then enter the castration resistance stage (CR) , At this time the volume of the tumor gradually increases
.
However, what is interesting is that when a variety of broad-spectrum antibiotics are used to remove the intestinal flora of mice, the growth rate of tumors in the CR stage will be significantly slower, indicating that the intestinal flora will affect the progression of prostate cancer
.
In addition, the results have also been verified in the LNCaP xenograft mouse model and the patient-derived LuCaP35 xenograft mouse model
.
Further analysis of 16S rDNA sequencing revealed that the relative abundance of Ruminococcus gnavus and Bacteroides acidifaciens increased significantly in castrated mice in CR stage
.
Through the method of fecal bacteria transplantation (FMT), it was further found that the bacteria from the CR stage of mice and R.
gnavus can maintain tumor growth, while the bacteria from wild-type mice inhibit the development of CRPC
.
However, the analysis of the systemic and tumor-infiltrating immune cells of the mice after castration revealed that the changes in the intestinal flora did not have a significant impact on the systemic and local immune responses of the mice
.
So, how does the intestinal flora affect the development of tumors? Considering that the intestinal flora will affect the metabolism of the host, the author speculates that the intestinal flora may affect the metabolism of the host and regulate the progression of tumors.
Based on this, the author analyzed the serum metabolome of mice
.
It was found that in castrated mice treated with antibiotics, the concentration of androgen-dehydroepiandrosterone (DHEA) and testosterone decreased significantly
.
Therefore, the author speculates that the two microorganisms enriched in the CR stage-R.
gnavus and B.
acidifaciens may have the ability to synthesize androgens
.
In order to verify this conjecture, the author co-cultured these two kinds of microorganisms with a series of intermediate products of androgen synthesis pathways in vitro, and found that these two kinds of bacteria can metabolize pregnenolone and hydroxyprogesterone, and convert them It is a downstream metabolite including DHEA and testosterone
.
Then, the author further verified it in vivo
.
By injecting deuterium-labeled pregnenolone into castrated mice treated with or without antibiotics, it was found that the circulating concentrations of deuterium-labeled DHEA and testosterone in antibiotic-treated mice were significantly lower than those without antibiotics Treated mice
.
The above in vivo and in vitro results indicate that microorganisms enriched in the CR stage of mice can participate in the metabolism of androgens and maintain the growth of prostate tumors in this way
.
Finally, the authors performed verification in HSPC (n=19) and CRPC (n=55) patients
.
Through metagenomic testing of rectal swabs, it was found that many microorganisms from the genera Ruminococcus and Bacteroides were enriched in CRPC patients, and genes related to the biosynthetic pathway of steroid hormones were also significantly enriched in CRPC patients
.
Further analysis showed that Ruminococcus sp.
DSM_100440, Ruminococcus sp.
OM05_10BH, Streptococcus vestibularis and Clostridiales bacterium VE202_14 were associated with poor clinical outcomes, while Prevotella spp.
BCRC_81118, Marseille_P4119 and 885 were associated with better clinical outcomes
.
Among them, in vitro experiments show that Ruminococcus sp.
DSM_100440 can metabolize pregnenolone and hydroxyprogesterone into androgens such as DHEA and testosterone
.
Then, the authors used two patient-derived organoids—CP50 (sensitive to androgen deprivation) and CP50C (insensitive to androgen deprivation) to detect the effects of Ruminococcus sp.
DSM_100440 on the host
.
It was found that the bacteria only promoted the expression of androgen receptor target genes in CP50
.
Moreover, abiraterone, a selective inhibitor of CYP17A1, can inhibit the conversion of pregnenolone into DHEA and testosterone by microorganisms
.
In addition, in the mouse model, Ruminococcus sp.
DSM_100440 can also maintain tumor growth, further confirming that Ruminococcus sp.
DSM_100440 plays a certain role in tumor development
.
In summary, the study found that intestinal bacteria can promote the development of prostate cancer by synthesizing androgens
.
However, the study did not reveal the mechanism by which the intestinal flora induces changes in androgen levels, and the specific mechanism by which related intestinal bacteria synthesize androgens
.
The above-mentioned problems are worthy of our further research to provide more treatment methods for patients with prostate cancer
.
It is worth mentioning that in the same period, Science magazine also published a commentary on the study by Professors John A.
McCulloch and Giorgio Trinchieri, Gut bacteria enable prostate cancer growth
.
Original link: https:// Platemaker: Instructions for reprinting on the 11th [Original article] BioArt original article, personal forwarding and sharing are welcome, reprinting without permission is prohibited, all published The copyright of the work is owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
