Prostate cancer screening with prostate‐specific antigen: Where are we going?

Albertsen, Peter C.

doi:10.1002/cncr.31140

Cited by 8 publications

(8 citation statements)

References 16 publications

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“…A reliable predictive maker of radiosensitivity can effectively guide personalized treatment decisions. Currently, glycosylated proteins have become one of the most common cancer biomarkers in the clinic, such as alpha-fetoprotein (AFP) for hepatocellular carcinoma [67], carcinoembryonic antigen (CEA) for colon cancer [68] and prostate specific antigen (PSA) for prostate cancer [69]. However, glycoprotein-related predictive maker for breast cancer, especially for radioresistant breast cancer, remains blank.…”

Section: Discussionmentioning

confidence: 99%

ALG3 contributes to stemness and radioresistance through regulating glycosylation of TGF-β receptor II in breast cancer

Sun

Guo

et al. 2021

J Exp Clin Cancer Res

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Background Radiotherapy is a conventional and effective local treatment for breast cancer. However, residual or recurrent tumors appears frequently because of radioresistance. Novel predictive marker and the potential therapeutic targets of breast cancer radioresistance needs to be investigated. Methods In this study, we screened all 10 asparagine-linked glycosylation (ALG) members in breast cancer patients’ samples by RT-PCR. Cell viability after irradiation (IR) was determined by CCK-8 assay and flow cytometry. The radiosensitivity of cell lines with different ALG3 expression was determined with the colony formation assay by fitting the multi-target single hit model to the surviving fractions. Cancer stem-like traits were assessed by RT-PCR, Western blot, and flow cytometry. The mechanisms of ALG3 influencing radiosensitivity was detected by Western blot and immunoprecipitation. And the effect of ALG3 on tumor growth after IR was verified in an orthotopic xenograft tumor models. The association of ALG3 with prognosis of breast cancer patients was confirmed by immunohistochemistry. Results ALG3 was the most significantly overexpressing gene among ALG family in radioresistant breast cancer tissue. Overexpression of ALG3 predicted poor clinicopathological characteristics and overall survival (OS), and early local recurrence-free survival (LRFS) in breast cancer patients. Upregulating ALG3 enhanced radioresistance and cancer stemness in vitro and in vivo. Conversely, silencing ALG3 increased the radiosensitivity and repressed cancer stemness in vitro, and more importantly inhibition of ALG3 effectively increased the radiosensitivity of breast cancer cells in vivo. Mechanistically, our results further revealed ALG3 promoted radioresistance and cancer stemness by inducing glycosylation of TGF-β receptor II (TGFBR2). Importantly, both attenuation of glycosylation using tunicamycin and inhibition of TGFBR2 using LY2109761 differentially abrogated the stimulatory effect of ALG3 overexpression on cancer stemness and radioresistance. Finally, our findings showed that radiation played an important role in preventing early recurrence in breast cancer patients with low ALG3 levels, but it had limited efficacy in ALG3-overexpressing breast cancer patients. Conclusion Our results suggest that ALG3 may serve as a potential radiosensitive marker, and an effective target to decrease radioresistance by regulating glycosylation of TGFBR2 in breast cancer. For patients with low ALG3 levels, radiation remains an effective mainstay therapy to prevent early recurrence in breast cancer.

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Section: Discussionmentioning

confidence: 99%

ALG3 contributes to stemness and radioresistance through regulating glycosylation of TGF-β receptor II in breast cancer

Sun

Guo

et al. 2021

J Exp Clin Cancer Res

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“…This is not without controversies. Most PSA—identified PCa are localized and usually low-grade disease, many of which never progress or become clinically relevant only after ~20 years [ 7 ]. This in itself raises the question of overdiagnosis of low-grade PCa, especially as the rapidly growing, difficult-to-treat, high-grade PCa are seldom found by PSA testing [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Most PSA—identified PCa are localized and usually low-grade disease, many of which never progress or become clinically relevant only after ~20 years [ 7 ]. This in itself raises the question of overdiagnosis of low-grade PCa, especially as the rapidly growing, difficult-to-treat, high-grade PCa are seldom found by PSA testing [ 7 , 8 ]. More so, being a highly sensitive biomarker, an abundance of false positives cannot be ruled out, and this is further compounded by the lack of consensual cut-off to delineate indolent from clinically relevant disease, thus yielding a pool of false positives and negatives [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…This in itself raises the question of overdiagnosis of low-grade PCa, especially as the rapidly growing, difficult-to-treat, high-grade PCa are seldom found by PSA testing [ 7 , 8 ]. More so, being a highly sensitive biomarker, an abundance of false positives cannot be ruled out, and this is further compounded by the lack of consensual cut-off to delineate indolent from clinically relevant disease, thus yielding a pool of false positives and negatives [ 7 , 8 ]. For example, one in five CRPC cases that eventually respond to chemotherapy would have been labeled ‘non-responders’ based on initial persistent elevated PSA level, that did not decline on immune checkpoint blockade therapy or only declined after week 12 of chemotherapy [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Concomitant High Apoptosis Inhibitor of Macrophage (AIM) and Low Prostate-Specific Antigen (PSA) Indicates Activated T Cell-Mediated Anticancer Immunity, Enhance Sensitivity to Pembrolizumab, and Elicit Good Prognosis in Prostate Cancer

et al. 2021

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Background: Despite its widespread use, the use of prostate-specific antigen (PSA) alone as a screening biomarker for prostate cancer (PCa) leads often to unwarranted prostate biopsy, over-diagnosis, and consequently, over-treatment, because of its limited specificity. There are reports that the apoptosis inhibitor of macrophage (AIM), secreted mainly by macrophages and epithelial cells, is upregulated during inflammation and facilitates immune recognition of cancerous cells by blocking human regulator of complement activation. Objective: These controversies around the PSA utility necessitate a reexamination of its use as a screening tool. More so, despite the suggested implication of AIM in anticancer immunosurveillance, there is a dearth of information on its role in therapy response, disease progression, and clinical outcomes of patients with PCa. These inform the present study to probe the nature and role of AIM/PSA signaling in anticancer immunity and prognosis in PCa. Methods: A combination of bioinformatics-aided statistical analyses, gene function annotation, and immune infiltrate analyses, coupled with tissue staining, and function assays, namely migration, invasion, and clonogenicity assays, we employed. Results: We demonstrated that AIM and PSA expression levels are inversely correlated in PCa clinical samples and cell lines, with AIMlowPSAhigh defining PCa, compared to AIMhighPSAlow in normal samples. Concomitant aberrant PSA and significantly suppressed AIM expression levels positively correlated with high-grade disease and characterized by advanced stage prostate cancer, regardless of mutation status. We found that a high PSA/AIM ratio is associated with disease recurrence in patients with prostate cancer but is equivocal for overall survival. In addition, PSA-associated AIM suppression is implicated in the enhanced ‘metastability’ of PCa and a high AIM/PSA ratio is associated with strong castration-induced regression. CRISPR-mediated AIM knockout was associated with higher PSA expression while ectopic expression of AIM significantly attenuated the migration and invasive capability of PC3 and DU145 cells. Interestingly, compared to normal samples, we observed that AIM, biomarkers of T-cell activation and M1 phenotype markers are co-suppressed in PCa samples. Conclusion: Herein, we demonstrate that AIM/CD5L binds to PSA and that a high PSA/AIM ratio defines advanced stage PCa (regardless of mutation status), is implicated in enhanced metastability, and associated with disease recurrence, while a high AIM/PSA ratio is associated with strong castration-induced regression. More so, the ectopic expression of AIM significantly enhances the anticancer effect of Pembrolizumab and elicits an increased CD8+ T-cell count in AIMhiPSAloPDL1+ PCa cases that are respondent to Pembrolizumab treatment.

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“…Furthermore, some study has shown that only 32.4% of patients with a PSA 4.0 ng/mL or higher had PCa [2]. Thus, current PSA screening is not cost-effective from a public health perspective [3] and many urologists are concerning for over-diagnosis of PCa with widespread serum PSA screening, which eventually could lead to overtreatment of PCa and its accompanied morbidities. And also, prostate biopsy under transrectal ultrasound (TRUS) is the only tool for diagnosing PCa, but it is invasive and can cause side effects such as infection and gross hematuria, and can give considerable discomfort to the patients during procedure.…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel non-invasive biological marker to overcome the shortcomings of PSA in diagnosis and risk stratification for prostate cancer: Initial prospective study of developmental endothelial locus-1 protein

Chung¹,

Kim²,

Ha³

et al. 2021

PLoS ONE

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Objective This prospective study sought to clarify the developmental endothelial locus-1 (Del-1) protein as values of diagnosis and risk stratification of prostate cancer (PCa). Design From February 2017 to December 2019, a total 458 patients who underwent transrectal ultrasound guided prostate biopsy or surgery of benign prostatic hyperplasia agreed to research of Del-1 protein. We prospectively compared and analyzed the Del-1 protein and prostate specific antigen (PSA) in relation to the patients’ demographic and clinicopathological characteristics. Results Mean age was 68.86±8.55 years. Mean PSA and Del-1 protein was 21.72±89.37, 0.099±0.145, respectively. Two hundred seventy-six (60.3%) patients were diagnosed as PCa. Among them, 181 patients underwent radical prostatectomy (RP). There were significant differences in Del-1 protein between benign and PCa group (0.066±0.131 vs 0.121±0.149, respectively, p<0.001). When we set the cut-off value of del-1 protein as 0.120, in patients with 3≤PSA≤8, positive predictive value and specificity of Del-1 protein (≥0.120) for predicting PCa were 88.9% (56/63) and 93.5% (101/108), respectively. Among 181 patients who underwent RP, there were significant differences in Del-1 protein according to stage (pT2 vs pT3a vs ≥pT3b) (0.113±0.078, 0.171±0.121, 0.227±0.161, respectively, p<0.001) and to Gleason score (6 (3+3) or 7 (3+4) vs 7 (4+3) or 8 (4+4) vs 9 or 10) (0.134±0.103, 0.150±0.109, 0.212±0.178, respectively, P = 0.044). Multivariate analysis showed that PSA, Del-1 protein and high Gleason score (≥9) were the independent prognostic factors for predicting higher pT stage (≥3b). Furthermore, age, PSA and Del-1 protein were independent prognostic factors for predicting significant PCa. Conclusion Patients with PCa showed higher expression of Del-1 protein than benign patients. Del-1 protein increased with the stage and Gleason score of PCa. Collaboration with PSA, Del-1 protein can be a non-invasive useful marker for diagnosis and risk stratification of PCa.

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Prostate cancer screening with prostate‐specific antigen: Where are we going?

Abstract: Current prostate‐specific antigen screening is not cost‐effective from a public health perspective. A new algorithm using genetic testing and imaging has yet to be developed. See also pages 507‐13.

Cited by 8 publications

References 16 publications

ALG3 contributes to stemness and radioresistance through regulating glycosylation of TGF-β receptor II in breast cancer

ALG3 contributes to stemness and radioresistance through regulating glycosylation of TGF-β receptor II in breast cancer

Concomitant High Apoptosis Inhibitor of Macrophage (AIM) and Low Prostate-Specific Antigen (PSA) Indicates Activated T Cell-Mediated Anticancer Immunity, Enhance Sensitivity to Pembrolizumab, and Elicit Good Prognosis in Prostate Cancer

Identification of a novel non-invasive biological marker to overcome the shortcomings of PSA in diagnosis and risk stratification for prostate cancer: Initial prospective study of developmental endothelial locus-1 protein

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