Molecular pathology of prostate cancer: a practical approach

Vlajnic, Tatjana; Bubendorf, Lukas

doi:10.1016/j.pathol.2020.10.003

Cited by 22 publications

(14 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…ERG and PTEN alterations represent the most frequent genomic events in primary PCa ( n = 333, cBioPortal [ 17 , 18 , 19 ], Figure 3A ). At the protein level, overexpression of ERG and loss of PTEN expression are robust surrogate markers for TMPRSS2–ERG fusion and homozygous PTEN deletion, respectively [ 20 , 21 , 22 ]. Therefore we assessed ERG and PTEN expression status by IHC in a large subset of our primary PCa cohort.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Prostate cancer patient‐derived organoids: detailed outcome from a prospective cohort of 81 clinical specimens

Servant

Garioni

Vlajnic

et al. 2021

The Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Patient-derived organoids (PDOs) represent promising preclinical models in various tumor types. In the context of prostate cancer (PCa), however, their establishment has been hampered by poor success rates, which impedes their broad use for translational research applications. Along with the necessity to improve culture conditions, there is a need to identify factors influencing outcomes and to determine how to assess success versus failure in organoid generation. In the present study, we report our unbiased efforts to generate PDOs from a cohort of 81 PCa specimens with diverse pathological and clinical features. We comprehensively analyzed histological features of each enrolled sample (Gleason score, tumor content, proliferation index) and correlated them with organoid growth patterns. We identified improved culture conditions favoring the generation of PCa organoids, yet no specific intrinsic tumor feature was broadly associated with sustained organoid growth. In addition, we performed phenotypic and molecular characterization of tumor-organoid pairs using immunohistochemistry, immunofluorescence, fluorescence in situ hybridization, and targeted sequencing. Morphological and immunohistochemical profiles of whole organoids altogether provided a fast readout to identify the most promising ones. Notably, primary samples were associated with an initial take-rate of 83% (n = 60/72) in culture, with maintenance of cancer cells displaying common PCa alterations, such as PTEN loss and ERG overexpression. These cancer organoids were, however, progressively overgrown by organoids with a benign-like phenotype. Finally, out of nine metastasis samples, we generated a novel organoid model derived from a hormone-naïve lung metastasis, which displays alterations in the PI3K/Akt and Wnt/β-catenin pathways and responds to androgen deprivation. Taken together, our comprehensive study explores determinants of outcome and highlights the opportunities and challenges associated with the establishment of stable tumor organoid lines derived from PCa patients.

show abstract

Section: Resultsmentioning

confidence: 99%

“…In contrast, other histological features associated with PCa aggressiveness (i.e. high GS and proliferation index [ 22 ]) were not enriched in samples growing with high efficiency, suggesting that they do not dictate organoid growth.…”

Section: Discussionmentioning

confidence: 99%

Prostate cancer patient‐derived organoids: detailed outcome from a prospective cohort of 81 clinical specimens

Servant

Garioni

Vlajnic

et al. 2021

The Journal of Pathology

Self Cite

View full text Add to dashboard Cite

show abstract

“…PTEN protein expression can also be assessed by IHC on formalin-fixed paraffin-embedded tissues (FFPE), offering the possibility to identify PTEN loss due to other mechanisms than genomic deletion [ 112 ]. Given the cost-effectiveness of IHC testing, systematic PTEN IHC analysis could be easily implemented in the diagnostic workup of patients with metastatic prostate cancer.…”

Section: Tissue and Methodsmentioning

confidence: 99%

Molecular Characterization of Prostate Cancers in the Precision Medicine Era

Giunta

Annaratone

Bollito

et al. 2021

Cancers

View full text Add to dashboard Cite

Prostate cancer (PCa) therapy has been recently revolutionized by the approval of new therapeutic agents in the metastatic setting. However, the optimal therapeutic strategy in such patients should be individualized in the light of prognostic and predictive molecular factors, which have been recently studied: androgen receptor (AR) alterations, PTEN-PI3K-AKT pathway deregulation, homologous recombination deficiency (HRD), mismatch repair deficiency (MMRd), and tumor microenvironment (TME) modifications. In this review, we highlighted the clinical impact of prognostic and predictive molecular factors in PCa patients’ outcomes, identifying biologically distinct subtypes. We further analyzed the relevant methods to detect these factors, both on tissue, i.e., immunohistochemistry (IHC) and molecular tests, and blood, i.e., analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Moreover, we discussed the main pros and cons of such techniques, depicting their present and future roles in PCa management, throughout the precision medicine era.

show abstract

“…Multiple mechanisms underlying the development of mPCa have been described [3,4], most of which confined to cancer epithelial cells. However, it has become evident that a crucial role in mPCa genesis is also played by the tumor microenvironment, consisting of non-immune and immune cells [1].…”

Section: Introductionmentioning

confidence: 99%

Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance

Antognelli

Mandarano

Prosperi

et al. 2021

Cancers

View full text Add to dashboard Cite

Metastatic prostate cancer (mPCa) is a disease for which to date there is not curative therapy. Even the recent and attractive immunotherapeutic approaches targeting PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance, have proved ineffective. A better understanding of the molecular mechanisms contributing to keep an immunosuppressive microenvironment associated with tumor progression and refractoriness to PD-L1 inhibitors is urgently needed. In the present study, by using gene silencing and specific activators or scavengers, we demonstrated, in mPCa cell models, that methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs), especially 5-hydro-5-methylimidazolone (MG-H1), and its metabolizing enzyme, glyoxalase 1 (Glo1), contribute to maintain an immunosuppressive microenvironment through MG-H1-mediated PD-L1 up-regulation and to promote cancer progression. Moreover, our findings suggest that this novel mechanism might be responsible, at least in part, of mPCa resistance to PD-L1 inhibitors, such as atezolizumab, and that targeting it may sensitize cells to this PD-L1 inhibitor. These findings provide novel insights into the mechanisms of mPCa immunosurveillance escape and help in providing the basis to foster in vivo research toward novel therapeutic strategies for immunotherapy of mPCa.

show abstract

Molecular pathology of prostate cancer: a practical approach

Cited by 22 publications

References 96 publications

Prostate cancer patient‐derived organoids: detailed outcome from a prospective cohort of 81 clinical specimens

Prostate cancer patient‐derived organoids: detailed outcome from a prospective cohort of 81 clinical specimens

Molecular Characterization of Prostate Cancers in the Precision Medicine Era

Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance

Contact Info

Product

Resources

About