Abstract:Gleason scoring is used within a five-tier risk stratification system to guide therapeutic decisions for patients with prostate cancer. This study aimed to compare the predictive performance of routine H&E or biomarker-assisted ISUP (International Society of Urological Pathology) grade grouping for assessing the risk of biochemical recurrence (BCR) and clinical recurrence (CR) in patients with prostate cancer. This retrospective study was an assessment of 114 men with prostate cancer who provided radical p… Show more
“…The differential detection of sortilin and syndecan-1 in well- and poorly-formed malignant glands aligns respectively with low- and high-grades of PCa 12 , 18 , suggesting that these proteins are central to PCa pathogenesis and disease progression. We hypothesised that the high expression of sortilin in low-grade PCa aligns with the regulation of glucose metabolism in LNCaP cells, while elevated syndecan-1 expression in high-grade PCa aligns with lipid metabolism in PC3 cells.…”
Section: Introductionmentioning
confidence: 78%
“…1 b). These immunolabelling patterns were representative of a large cohort of tissue samples from PCa patients (n > 100), which were previously used to validate these markers where there was a significant change in sortilin and syndecan-1 expression and distribution that enabled more reliable IHC-assisted grading and better stratification of patients 12 , 18 . Figure 1 Sortilin and syndecan-1 immunolabelling depicts pathogenesis of PCa, which aligns with immunofluorescence in prostate cell line models.…”
Prostate cancer (PCa) development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor expression and signalling. Defining the molecular mechanism that underpins this metabolic programming will have direct significance for patients with PCa who have a poor prognosis. Here we show that there is a dynamic balance between sortilin and syndecan-1, that reports on different metabolic phenotypes. Using tissue microarrays, we demonstrated by immunohistochemistry that sortilin was highly expressed in low-grade cancer, while syndecan-1 was upregulated in high-grade disease. Mechanistic studies in prostate cell lines revealed that in androgen-sensitive LNCaP cells, sortilin enhanced glucose metabolism by regulating GLUT1 and GLUT4, while binding progranulin and lipoprotein lipase (LPL) to limit lipid metabolism. In contrast, in androgen-insensitive PC3 cells, syndecan-1 was upregulated, interacted with LPL and colocalised with β3 integrin to promote lipid metabolism. In addition, androgen-deprived LNCaP cells had decreased expression of sortilin and reduced glucose-metabolism, but increased syndecan-1 expression, facilitating interactions with LPL and possibly β3 integrin. We report a hitherto unappreciated molecular mechanism for PCa, which may have significance for disease progression and how androgen-deprivation therapy might promote castration-resistant PCa.
“…The differential detection of sortilin and syndecan-1 in well- and poorly-formed malignant glands aligns respectively with low- and high-grades of PCa 12 , 18 , suggesting that these proteins are central to PCa pathogenesis and disease progression. We hypothesised that the high expression of sortilin in low-grade PCa aligns with the regulation of glucose metabolism in LNCaP cells, while elevated syndecan-1 expression in high-grade PCa aligns with lipid metabolism in PC3 cells.…”
Section: Introductionmentioning
confidence: 78%
“…1 b). These immunolabelling patterns were representative of a large cohort of tissue samples from PCa patients (n > 100), which were previously used to validate these markers where there was a significant change in sortilin and syndecan-1 expression and distribution that enabled more reliable IHC-assisted grading and better stratification of patients 12 , 18 . Figure 1 Sortilin and syndecan-1 immunolabelling depicts pathogenesis of PCa, which aligns with immunofluorescence in prostate cell line models.…”
Prostate cancer (PCa) development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor expression and signalling. Defining the molecular mechanism that underpins this metabolic programming will have direct significance for patients with PCa who have a poor prognosis. Here we show that there is a dynamic balance between sortilin and syndecan-1, that reports on different metabolic phenotypes. Using tissue microarrays, we demonstrated by immunohistochemistry that sortilin was highly expressed in low-grade cancer, while syndecan-1 was upregulated in high-grade disease. Mechanistic studies in prostate cell lines revealed that in androgen-sensitive LNCaP cells, sortilin enhanced glucose metabolism by regulating GLUT1 and GLUT4, while binding progranulin and lipoprotein lipase (LPL) to limit lipid metabolism. In contrast, in androgen-insensitive PC3 cells, syndecan-1 was upregulated, interacted with LPL and colocalised with β3 integrin to promote lipid metabolism. In addition, androgen-deprived LNCaP cells had decreased expression of sortilin and reduced glucose-metabolism, but increased syndecan-1 expression, facilitating interactions with LPL and possibly β3 integrin. We report a hitherto unappreciated molecular mechanism for PCa, which may have significance for disease progression and how androgen-deprivation therapy might promote castration-resistant PCa.
“…Apart from the aforementioned diagnostic tests, most respondents in this survey also emphasized the significance of prognosis, therapeutic options, and patient management as important aspects for future melanoma studies. Furthermore, the discovery of new biomarkers that can report on the primary disease pathogenesis could enhance our understanding of melanoma biology to overcome these issues, guiding a precision medicine approach for patients [ 37 , 38 ]. Thus, newly identified biomarkers should be evaluated in the context of their biological relevance to the primary pathogenesis, while also considering the heterogeneity of the disease (accounting for tumor variation and clonal evolution) [ 7 , 25 , 39 , 40 ], before their potential clinical utility can be truly determined, as different subtypes of melanoma can exhibit distinct genotypes and immunophenotypes [ 30 , 41 ].…”
Background: Early diagnosis is the key to improving outcomes for patients with melanoma, and this requires a standardized histological assessment approach. The objective of this survey was to understand the challenges faced by clinicians when assessing melanoma cases, and to provide a perspective for future studies. Methods: Between April 2022 and February 2023, national and international dermatologists, pathologists, general practitioners, and laboratory managers were invited to participate in a six-question online survey. The data from the survey were assessed using descriptive statistics and qualitative responses. Results: A total of 54 responses were received, with a 51.4% (n = 28) full completion rate. Of the respondents, 96.4% reported ambiguity in their monthly melanoma diagnosis, and 82.1% routinely requested immunohistochemistry (IHC) testing to confirm diagnosis. SOX10 was the most frequently requested marker, and most respondents preferred multiple markers over a single marker. Diagnostic and prognostic tests, as well as therapeutic options and patient management, were all identified as important areas for future research. Conclusions: The respondents indicated that the use of multiple IHC markers is essential to facilitate diagnostic accuracy in melanoma assessment. Survey responses indicate there is an urgent need to develop new biomarkers for clinical decision making at multiple critical intervention points.
High-grade prostatic intraepithelial neoplasia (HGPIN) is a well-characterised precursor lesion in prostate cancer. The term atypical intraductal proliferations (AIP) describes lesions with features that are far too atypical to be considered HGPIN, yet insufficient to be diagnosed as intraductal carcinoma of the prostate (IDCP). Here, a panel of biomarkers was assessed to provide insights into the biological relationship between IDCP, HGPIN, and AIP and their relevance to current clinicopathological recommendations. Tissue samples from 86 patients with prostate cancer were assessed by routine haematoxylin and eosin staining and immunohistochemistry (IHC) with a biomarker panel (Appl1/Sortilin/Syndecan-1) and a PIN4 cocktail (34βE12+P63/P504S). Appl1 strongly labelled atypical secretory cells, effectively visualising intraductal lesions. Sortilin labelling was moderate-to-strong in > 70% of cases, while Syndecan-1 was moderate-to-strong in micropapillary HGPIN/AIP lesions (83% cases) versus flat/tufting HGPIN (≤ 20% cases). Distinct biomarker labelling patterns for atypical intraductal lesions of the prostate were observed, including early atypical changes (flat/tufting HGPIN) and more advanced atypical changes (micropapillary HGPIN/AIP). Furthermore, the biomarker panel may be used as a tool to overcome the diagnostic uncertainty surrounding AIP by supporting a definitive diagnosis of IDCP for such lesions displaying the same biomarker pattern as cribriform IDCP.
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