Gut microbiome and prostate cancer Fujita, Kazutoshi; Matsushita, Makoto; Banno, Eri ...
International journal of urology,
August 2022, Letnik:
29, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The gut microbiome is linked to several diseases such as Alzheimer's disease, rheumatoid arthritis, and colon cancer. The gut microbiome is also associated with the modulation of immune function, ...resulting in a different response to immune checkpoint therapy. The gut microbiome differs according to lifestyle, diet, sex, race, genetic background, and country. Lifestyle, especially diet, plays an important role in the development and progression of prostate cancer. Recent studies have revealed a connection between the gut microbiome and prostate cancer. A high‐fat diet causes gut dysbiosis and gut bacterial metabolites, such as short‐chain fatty acids and phospholipids that enter systemic circulation result in promoting prostate cancer growth. Additionally, the gut microbiota can serve as a source of testosterone, which affects prostate cancer progression. Men with castration‐resistant prostate cancer have an increased abundance of gut bacteria with androgenic functions. Men with high‐risk prostate cancer share a specific gut microbial profile and profiling gut microbiota could be a potentially effective tool to screen men with high‐risk prostate cancer. Lifestyle modifications can improve the gut microbiome. Furthermore, altering the gut microbiome using prebiotic or probiotic interventions may prevent or delay prostate cancer development. Further study into the “Gut–Prostate Axis” would help in the discovery of new strategies for the prevention, screening, and treatment of prostate cancer.
Understanding the genomic profiling of prostate cancer is crucial, owing to the emergence of precision medicine to guide therapeutic approaches. Over the last decade, integrative genomic profiling of ...prostate tumors has provided insights that improve the understanding and treatment of the disease. Minimally invasive liquid biopsy procedures have emerged to investigate cancer-related molecules with the advantage of detecting heterogeneity as well as acquired resistance in cancer. The metastatic castration-resistant prostate cancer (mCRPC) tumors have a highly complex genomic landscape compared to primary prostate tumors; a number of mCRPC harbor clinically actionable molecular alterations, including DNA damage repair (
,
and
) and PTEN/phosphoinositide 3-kinase signaling. Heterogeneity in the genomic landscape of prostate cancer has become apparent and genomic alterations of
,
,
, and cell cycle pathway are associated with poor clinical outcomes in patients. Prostate cancer with mutant
shows a distinct pattern of genomic alterations, associating with better clinical outcomes. Several genomic profiling tests, which can be used in the clinic, are approved by the U.S. Food and Drug Administration, including MSK-IMPACT, FoundationOne CDx, and FoundationOne Liquid CDx. Here, we review emerging evidence for genomic profiling of prostate cancer, especially focusing on associations between genomic alteration and clinical outcome, liquid biopsy, and actionable molecular alterations.
The introduction of novel therapeutic agents for advanced prostate cancer has led to a wide range of treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC). In ...the past decade, new treatment options for mCRPC, including abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, radium-223,
Lu-PSMA-617, and Olaparib, have demonstrated a survival benefit in phase 3 trials. Bone-modifying agents have become part of the overall treatment strategy for mCRPC, in which denosumab and zoledronic acid reduce skeletal-related events. Recently, androgen receptor-signaling inhibitors (ARSIs) and docetaxel have been used upfront against metastatic castration-sensitive prostate cancer. Further, triplet therapy with ARSI, docetaxel, and androgen deprivation therapy is emerging. However, cross-resistance may occur between these treatments, and the optimal treatment sequence must be considered. The sequential administration of ARSIs, such as abiraterone and enzalutamide, is associated with limited efficacy; however, cabazitaxel is effective for patients with mCRPC who were previously treated with docetaxel and had disease progression during treatment with ARSI. Radioligand therapy with
Lu-PSMA-617 is a new effective class of therapy for patients with advanced PSMA-positive mCRPC. Tumors with gene alterations that affect homologous recombination repair, such as
and
alterations, are sensitive to poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors in mCRPC. This review sought to highlight recent advances in systemic therapy for mCRPC and strategies to support patient selection and treatment sequencing.
Objective
18
F-labeled prostate-specific membrane antigen (PSMA) ligand,
18
FPSMA-1007, has the benefit of a higher synthetic yield and minimal excretion in the urine. High detection efficacy was ...reported in biochemical recurrence (BCR) of prostate cancer after radical prostatectomy. Thus, we evaluated the preliminary diagnostic utility of
18
FPSMA-1007 PET in patients with prostate cancer, focusing on the BCR which is not detected on conventional imaging.
Methods
We enrolled a total of 28 patients (age 51–79 years) with BCR of prostate cancer. BCR was defined as a continuous increase in PSA after radical prostatectomy or radiation therapy without any apparent recurrent lesions on conventional diagnostic imaging (CT and bone scintigraphy). PSMA-PET scanning was performed approximately 60 min after intravenous injection of
18
FPSMA-1007 (259 ± 37 MBq). PSMA-PET images were evaluated for lesion detection as well as its relation to PSA values and location.
Results
Abnormal uptake, which was suspected to be recurrence or metastasis, was detected in 92.9% (26/28) of patients with BCR. The SUVmax was 8.4 ± 6.4 in local recurrence, 11.5 ± 11.8 in pelvic lymph nodes (LN), and 4.1 ± 1.6 in bone metastasis. The detection rates were 66.7% in the PSA group-1 (0.1–0.5 ng/mL), 85.7% in the PSA group-2 (0.5–1.0 ng/mL), and 100% in the PSA group-3 (above 1.0 ng/mL). Among the PET-positive BCR patients (
n
= 26), local recurrence was detected in 57.7% (15/26), pelvic LN in 42.3% (11/26), and bone metastasis in 15.4% (4/26). In 53% (8/15) of BCR patients who were suspected of local recurrence, focal uptake was detected adjacent to the bladder on
18
FPSMA-1007 PET. This suggested the significant advantage of having minimal physiological urine excretion.
Conclusions
18
FPSMA-1007 PET showed a high detection rate in recurrent and metastatic lesions. In patients with BCR, its high detection led to suitable treatment strategies, such as salvage radiation therapy or surgical removal of recurrent lymph nodes.
Trial registration
(UMIN Clinical Trials Registry) UMIN000037697.
Proteomic analysis of urinary extracellular vesicles (EVs) is a powerful approach to discover potential bladder cancer (BCa) biomarkers, however urine contains numerous EVs derived from the kidney ...and normal urothelial epithelium, which can obfuscate information related to BCa cell‐derived EVs. In this study, we combined proteomic analysis of urinary EVs and tissue‐exudative EVs (Te‐EVs), which were isolated from culture medium of freshly resected viable BCa tissues. Urinary EVs were isolated from urine samples of 11 individuals (7 BCa patients and 4 healthy individuals), and Te‐EVs were isolated from 7 BCa tissues. We performed tandem mass tag (TMT)‐labeling liquid chromatography (LC‐MS/MS) analysis for both urinary EVs and Te‐EVs and identified 1960 proteins in urinary EVs and 1538 proteins in Te‐EVs. Most of the proteins identified in Te‐EVs were also present in urinary EVs (82.4%), with 55 of these proteins showing upregulated levels in the urine of BCa patients (fold change > 2.0; P < .1). Among them, we selected 22 membrane proteins as BCa biomarker candidates for validation using selected reaction monitoring/multiple reaction monitoring (SRM/MRM) analysis on urine samples from 70 individuals (40 BCa patients and 30 healthy individuals). Six urinary EV proteins (heat‐shock protein 90, syndecan‐1, myristoylated alanine‐rich C‐kinase substrate (MARCKS), MARCKS‐related protein, tight junction protein ZO‐2, and complement decay‐accelerating factor) were quantified using SRM/MRM analysis and validated as significantly upregulated in BCa patients (P < .05). In conclusion, the novel strategy that combined proteomic analysis of urinary EVs and Te‐EVs enabled selective detection of urinary BCa biomarkers.
Proteomic analysis of urinary extracellular vesicles (EVs) is a powerful approach to discovering potential BCa biomarkers, however urine contains numerous EVs derived from kidney and normal urothelial epithelium that could dilute the information of cancer BCa cell‐derived EVs. In this study, we performed combined proteomic analysis of both urinary EVs and tissue‐extracted EVs (Te‐EVs) to identify reliable BCa biomarkers. This novel strategy presented here identified reliable urinary EV biomarker proteins exhibiting high levels of specificity and sensitivity for non‐invasive BCa detection.
Altered prostate-specific antigen (PSA) glycosylation patterns can be useful biomarkers in detecting high-grade prostate cancer (HGPC). The microfluidic immunoassay system can analyse α2,3-linked ...sialylated PSA (α2,3-Sia-PSA) and α1,6-linked fucosylated PSA (α1,6-Fuc-PSA) using different lectins, Mackkia amurensis agglutinin and Pholiota squarrosa lectin, respectively. Here, we investigated the diagnostic value of simultaneous analysis of α2,3-Sia-PSA and α1,6-Fuc-PSA for the detection of HGPC.
Men with serum PSA levels of 4-20 ng/mL who underwent prostate biopsy were included. The model to predict HGPC (Gleason grade ≥2) was constructed by multivariate logistic regression analysis, in combination with α2,3-Sia-PSA and α1,6-Fuc-PSA (SF index).
In the development cohort (n = 150), the SF index showed good discrimination for HGPC (area under the receiver-operating curve (AUC) 0.842; 95% confidence interval (CI) 0.782-0.903), compared to the single PSA test (AUC 0.632, 95% CI 0.543-0.721), α2,3-Sia-PSA (AUC 0.711, 95% CI 0.629-0.793) and α1,6-Fuc-PSA (AUC 0.738, 95% CI 0.657-0.819). Decision-curve analysis showed the superior benefit of the SF index. In the validation cohort (n = 57), the SF index showed good discrimination for HGPC (AUC 0.769, 95% CI 0.643-0.895).
The SF index could differentiate HGPC, providing useful information for decision making for prostate biopsy in men with abnormal PSA levels.
Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut microbiota is known to change with dietary composition and body ...type, we used prostate-specific
knockout mice as a prostate cancer model to investigate whether there is a gut microbiota-mediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer-bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including
and
, inhibited prostate cancer cell proliferation, and reduced prostate
expression and circulating insulin-like growth factor-1 (IGF1) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGF1 receptor, were suppressed by Abx administration. IGF1 directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1
. Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF1 levels. In humans, IGF1 was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment. SIGNIFICANCE: These results suggest that intestinal bacteria, acting through short-chain fatty acids, regulate systemic and local prostate IGF1 in the host, which can promote proliferation of prostate cancer cells.
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