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15 pages, 3069 KiB

Open AccessArticle

Genomic Landscape Alterations in Primary Tumor and Matched Lymph Node Metastasis in Hormone-Naïve Prostate Cancer Patients

by Giorgio Ivan Russo, Paolo Bonacci, Dalida Bivona, Grete Francesca Privitera, Giuseppe Broggi, Rosario Caltabiano, Jessica Vella, Arturo Lo Giudice, Maria Giovanna Asmundo, Sebastiano Cimino, Giuseppe Morgia, Stefania Stefani and Nicolò Musso

Cancers 2022, 14(17), 4212; https://doi.org/10.3390/cancers14174212 - 30 Aug 2022

Cited by 4 | Viewed by 1557

Abstract

Background: Prostate cancer (PCa) is a disease with a wide range of clinical manifestations. Up to the present date, the genetic understanding of patients with favorable or unfavorable prognosis is gaining interest for giving the appropriate tailored treatment. We aimed to investigate genetic [...] Read more.

Background: Prostate cancer (PCa) is a disease with a wide range of clinical manifestations. Up to the present date, the genetic understanding of patients with favorable or unfavorable prognosis is gaining interest for giving the appropriate tailored treatment. We aimed to investigate genetic changes associated with lymph node metastasis in a cohort of hormone-naïve Pca patients. Methods: We retrospectively analyzed data from 470 patients who underwent surgery for PCa between 2010 and 2020 at the Department of Urology, University of Catania. Inclusion criteria were patients with lymph node metastasis and patients with PCa with extra capsular extension (pT3) and negative lymph node metastasis. The final cohort consisted of 17 different patients (11 PCa with lymph node metastasis and 6 PCa without lymph node metastasis). Through the cBioPortal online tool, we analyzed gene alterations and their correlations with clinical factors. Results: A total of 688 intronic, synonym and nonsynonym mutations were sequenced. The gene with the most sequenced mutations was ERBB4 (83 mutations, 12% of 688 total), while the ones with the lower percentage of mutations were AKT1, FGFR2 and MLH1 (1 mutation alone, 0.14%). Conclusion: In the present study we found mostly concordance concerning the ERBB4 mutation between both primary PCa samples and matched lymph node metastasis, underlining that the identification of alterations in the primary tumor is extremely important for cancer prognosis prediction. Full article

(This article belongs to the Special Issue Bio-Pathological Markers for the Diagnosis and Therapy of Cancers, Volume II)

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16 pages, 2463 KiB

Open AccessArticle

Molecular Characterization of Cancer Associated Fibroblasts in Prostate Cancer

by Giovanni Vitale, Michele Caraglia, Volker Jung, Jörn Kamradt, Davide Gentilini, Maria Teresa Di Martino, Alessandra Dicitore, Marianna Abate, Pierosandro Tagliaferri, Annalisa Itro, Matteo Ferro, Raffaele Balsamo, Marco De Sio, Gaetano Facchini, Luca Persani, Kai Schmitt, Matthias Saar, Michael Stöckle, Gerhard Unteregger and Silvia Zappavigna

Cancers 2022, 14(12), 2943; https://doi.org/10.3390/cancers14122943 - 14 Jun 2022

Cited by 4 | Viewed by 2104

Abstract

Background: Stromal components surrounding epithelial cancer cells seem to play a pivotal role during epithelial-to-mesenchymal transition (EMT), tumor invasion, and metastases. To identify the molecular mechanisms underlying tumor–stroma interactions may yield novel therapeutic targets for prostate cancer. Methods: Gene expression profile of prostate-cancer [...] Read more.

Background: Stromal components surrounding epithelial cancer cells seem to play a pivotal role during epithelial-to-mesenchymal transition (EMT), tumor invasion, and metastases. To identify the molecular mechanisms underlying tumor–stroma interactions may yield novel therapeutic targets for prostate cancer. Methods: Gene expression profile of prostate-cancer associated fibroblast (PCAF) and prostate non-cancer associated fibroblast (PNAF) cells isolated from radical prostatectomy was performed by Illumina, analyzed, and further processed by Ingenuity^®: IPA^® software. qRT-PCR was performed on an independent set of 17 PCAF, 12 PNAF, and 12 fibroblast cell lines derived from patients with benign prostatic hyperplasia (BPHF). Results: Using microarray analysis, we found six upregulated genes and two downregulated genes in PCAFs compared to PNAFs. To validate microarray results, we performed qRT-PCR for the most significantly regulated genes involved in the modulation of proliferation and androgen resistance on an independent set of PNAF, PCAF, and BHPF samples. We confirmed the increased expression of SCARB1, MAPK3K1, and TGF-β as well as the decreased expression of S100A10 in PCAFs compared to PNAFs and BPHFs. Conclusions: These results provide strong evidence that the observed changes in the gene expression profile of PCAFs can contribute to functional alteration of adjacent prostate cancer cells. Full article

(This article belongs to the Special Issue Bio-Pathological Markers for the Diagnosis and Therapy of Cancers, Volume II)

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19 pages, 2935 KiB

Open AccessArticle

Bottom-Up Approach to the Discovery of Clinically Relevant Biomarker Genes: The Case of Colorectal Cancer

by Faddy Kamel, Nathalie Schneider, Pasha Nisar and Mikhail Soloviev

Cancers 2022, 14(11), 2654; https://doi.org/10.3390/cancers14112654 - 27 May 2022

Viewed by 1682

Abstract

Traditional approaches to genome-wide marker discovery often follow a common top-down strategy, where a large scale ‘omics’ investigation is followed by the analysis of functional pathways involved, to narrow down the list of identified putative biomarkers, and to deconvolute gene expression networks, or [...] Read more.

Traditional approaches to genome-wide marker discovery often follow a common top-down strategy, where a large scale ‘omics’ investigation is followed by the analysis of functional pathways involved, to narrow down the list of identified putative biomarkers, and to deconvolute gene expression networks, or to obtain an insight into genetic alterations observed in cancer. We set out to investigate whether a reverse approach would allow full or partial reconstruction of the transcriptional programs and biological pathways specific to a given cancer and whether the full or substantially expanded list of putative markers could thus be identified by starting with the partial knowledge of a few disease-specific markers. To this end, we used 10 well-documented differentially expressed markers of colorectal cancer (CRC), analyzed their transcription factor networks and biological pathways, and predicted the existence of 193 new putative markers. Incredibly, the use of a validation marker set of 10 other completely different known CRC markers and the same procedure resulted in a very similar set of 143 predicted markers. Of these, 138 were identical to those found using the training set, confirming our main hypothesis that a much-expanded set of disease markers can be predicted by starting with just a small subset of validated markers. Further to this, we validated the expression of 42 out of 138 top-ranked predicted markers experimentally using qPCR in surgically removed CRC tissues. We showed that 41 out of 42 mRNAs tested have significantly altered levels of mRNA expression in surgically excised CRC tissues. Of the markers tested, 36 have been reported to be associated with aspects of CRC in the past, whilst only limited published evidence exists for another three genes (BCL2, PDGFRB and TSC2), and no published evidence directly linking genes to CRC was found for CCNA1, SHC1 and TGFB3. Whilst we used CRC to test and validate our marker discovery strategy, the reported procedures apply more generally to cancer marker discovery. Full article

(This article belongs to the Special Issue Bio-Pathological Markers for the Diagnosis and Therapy of Cancers, Volume II)

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19 pages, 2264 KiB

Open AccessArticle

Prognostic Value of IGF2 mRNA-Binding Protein 3 (IGF2BP3) Intratumoral Expression in Melanoma Patients at the Time of Diagnosis: Comparative Analysis of RT-qPCR Versus Immunohistochemistry

by Beatriz Sánchez-Sendra, Silvia Pérez-Debén, José F. González-Muñoz, Amelia Murgui and Carlos Monteagudo

Cancers 2022, 14(9), 2319; https://doi.org/10.3390/cancers14092319 - 07 May 2022

Cited by 1 | Viewed by 1870

Abstract

Screening for prognostic biomarkers is crucial for clinical melanoma management. Insulin-like growth factor-II mRNA-binding protein 3 (IGF2BP3) has emerged as a potential melanoma diagnostic and prognostic biomarker. It is commonly tested by immunohistochemistry (IHC). Our study retrospectively examines IGF2BP3 mRNA and protein expression [...] Read more.

Screening for prognostic biomarkers is crucial for clinical melanoma management. Insulin-like growth factor-II mRNA-binding protein 3 (IGF2BP3) has emerged as a potential melanoma diagnostic and prognostic biomarker. It is commonly tested by immunohistochemistry (IHC). Our study retrospectively examines IGF2BP3 mRNA and protein expression in primary melanomas, their correlation with clinicopathologic factors, clinical outcome, and selected miRNAs expression, and their efficiency in predicting melanoma progression and survival. RT-qPCR and IHC on IGF2BP3 expression were performed in 61 cryopreserved and 63 formalin-fixed paraffin-embedded primary melanomas, respectively, and correlated to clinicopathologic factors, distant metastasis-free survival (DMFS), and melanoma -specific survival (MSS). The correlation between RT-qPCR and IHC was significant but moderate. IGF2BP3 mRNA showed a stronger association with clinicopathologic factors (Breslow thickness, ulceration, mitosis rate, growth phase, development of metastasis, and melanoma-specific survival) than its protein counterpart. Interestingly, higher IGF2BP3 mRNA expression was detected in primary melanomas that further metastasized to distant sites and was an independent prognostic factor for the risk of unfavorable DMFS and MSS. RT-qPCR outperformed IHC in sensitivity and in predicting worse clinical outcomes. Therefore, RT-qPCR may successfully be implemented for routine IGF2BP3 assessing for the selection of melanoma patients with a higher risk of developing distant metastasis and dying of melanoma. Full article

(This article belongs to the Special Issue Bio-Pathological Markers for the Diagnosis and Therapy of Cancers, Volume II)

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14 pages, 2730 KiB

Open AccessArticle

SRPX Emerges as a Potential Tumor Marker in the Extracellular Vesicles of Glioblastoma

by Elisabet Ampudia-Mesias, Samia El-Hadad, Charles Scott Cameron, Adelheid Wöhrer, Thomas Ströbel, Nurten Saydam and Okay Saydam

Cancers 2022, 14(8), 1984; https://doi.org/10.3390/cancers14081984 - 14 Apr 2022

Cited by 2 | Viewed by 2077

Abstract

Extracellular vesicles (EVs) may be used as a non-invasive screening platform to discover markers associated with early diagnosis, prognosis, and treatment response. Such an approach is invaluable for diseases such as glioblastoma, for which only a few non-invasive diagnostic or prognostic markers are [...] Read more.

Extracellular vesicles (EVs) may be used as a non-invasive screening platform to discover markers associated with early diagnosis, prognosis, and treatment response. Such an approach is invaluable for diseases such as glioblastoma, for which only a few non-invasive diagnostic or prognostic markers are available. We used mass spectrometry to analyze proteomics profiles of EVs derived from four glioblastoma cell lines and human primary astrocytes (HPAs) and found that SRPX is the only protein enriched in the majority of glioblastoma EVs that was absent in the HPA-derived EVs. Then, we evaluated the relationship between SRPX protein expression and tumor grade using immunohistochemical staining (IHC) and performed colony formation and viability assays to analyze the possible function of SRPX in glioblastoma. SRPX mRNA and protein expression were associated with tumor grade. Moreover, temozolomide (TMZ)-resistant tumor tissues showed highly positive SRPX staining, compared to all other tumor grades. Additionally, glioblastoma cells displayed enhanced SRPX gene expression when exposed to TMZ. Knockdown of SRPX gene expression via siRNA inhibited cell viability. Taken together, the results of this study suggest that SRPX can be used as a novel tumor marker for diagnostic and prognostic purposes and can also be a therapeutic target for glioblastomas. Full article

(This article belongs to the Special Issue Bio-Pathological Markers for the Diagnosis and Therapy of Cancers, Volume II)

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18 pages, 13617 KiB

Open AccessArticle

Lymph but Not Blood Vessel Invasion Is Independent Prognostic in Lung Cancer Patients Treated by VATS-Lobectomy and Might Represent a Future Upstaging Factor for Early Stages

by Melanie Biesinger, Nele Eicken, Alexander Varga, Michael Weber, Milos Brndiar, Georg Erd, Peter Errhalt, Klaus Hackner, Sarah Hintermair, Alexander Petter-Puchner, Axel Scheed, Elisabeth Stubenberger and Bahil Ghanim

Cancers 2022, 14(8), 1893; https://doi.org/10.3390/cancers14081893 - 08 Apr 2022

Cited by 3 | Viewed by 1970

Abstract

Lung cancer is the most frequent cause of cancer-related death worldwide. The patient’s outcome depends on tumor size, lymph node involvement and metastatic spread at the time of diagnosis. The prognostic value of lymph and blood vessel invasion, however, is still insufficiently investigated. [...] Read more.

Lung cancer is the most frequent cause of cancer-related death worldwide. The patient’s outcome depends on tumor size, lymph node involvement and metastatic spread at the time of diagnosis. The prognostic value of lymph and blood vessel invasion, however, is still insufficiently investigated. We retrospectively examined the invasion of lymph vessels and blood vessels separately as two possible prognostic factors in 160 patients who underwent a video-assisted thoracoscopic lobectomy for non-small-cell lung cancer at our institution between 2014 and 2019. Lymph vessel invasion was significantly associated with the UICC stage, lymph node involvement, tumor dedifferentiation, blood vessel invasion and recurrence. Blood vessel invasion tended to be negative prognostic, but missed the level of significance (p = 0.108). Lymph vessel invasion, on the other hand, proved to be a prognostic factor for both histological subtypes, adenocarcinoma (p < 0.001) as well as squamous cell carcinoma (p = 0.018). After multivariate analysis apart from the UICC stage, only lymph vessel invasion remained independently prognostic (p = 0.018). Remarkably, we found analogue survival curve progressions of patients with stage I, with lymph vessel invasion, compared to stage II non-small-cell lung cancer. After further validation in prospective studies, lymph vessel invasion might be considered as an upstaging factor in resectable lung cancer. Especially in the early-stage of the disease, it might represent an additional risk factor to consider adjuvant therapy after surgical resection. Full article

(This article belongs to the Special Issue Bio-Pathological Markers for the Diagnosis and Therapy of Cancers, Volume II)

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14 pages, 1982 KiB

Open AccessArticle

Circulating Levels of the Cardiovascular Biomarkers ST2 and Adrenomedullin Predict Outcome within a Randomized Phase III Lung Cancer Trial (RASTEN)

by Emelie Gezelius, Pär-Ola Bendahl, Widet Gallo, Kelin Gonçalves de Oliveira, Lars Ek, Bengt Bergman, Jan Sundberg, Olle Melander and Mattias Belting

Cancers 2022, 14(5), 1307; https://doi.org/10.3390/cancers14051307 - 03 Mar 2022

Cited by 2 | Viewed by 2672

Abstract

Cardiovascular comorbidity is common in small cell lung cancer (SCLC) and may significantly affect treatment tolerability and patient outcome. Still, there are no established biomarkers for objective and dynamic assessment as a tool for improved treatment decisions. We have investigated circulating levels of [...] Read more.

Cardiovascular comorbidity is common in small cell lung cancer (SCLC) and may significantly affect treatment tolerability and patient outcome. Still, there are no established biomarkers for objective and dynamic assessment as a tool for improved treatment decisions. We have investigated circulating levels of midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial-natriuretic peptide (MR-proANP), copeptin (surrogate for vasopressin) and suppression-of-tumorigenicity-2 (ST2), all known to correlate with various aspects of cardiovascular function, in a SCLC cohort (N = 252) from a randomized, controlled trial (RASTEN). For all measured biomarkers, protein levels were inversely associated with survival, particularly with ST2 and MR-proADM, where the top versus bottom quartile was associated with an adjusted hazard ratio of 2.40 (95% CI 1.44–3.98; p = 0.001) and 2.18 (95% CI 1.35–3.51; p = 0.001), respectively, in the entire cohort, and 3.43 (95% CI 1.73–6.79; p < 0.001) and 3.49 (95% CI 1.84–6.60; p < 0.001), respectively, in extensive disease patients. A high combined score of MR-proADM and ST2 was associated with a significantly reduced median OS of 7.0 months vs. 14.9 months for patients with a low combined score. We conclude that the cardiovascular biomarkers MR-proADM and ST2 strongly correlate with survival in SCLC, warranting prospective studies on the clinical utility of MR-proADM and ST2 for improved, individualized treatment decisions. Full article

(This article belongs to the Special Issue Bio-Pathological Markers for the Diagnosis and Therapy of Cancers, Volume II)

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Review

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21 pages, 3091 KiB

Open AccessReview

The Role of Dielectrophoresis for Cancer Diagnosis and Prognosis

by Giorgio Ivan Russo, Nicolò Musso, Alessandra Romano, Giuseppe Caruso, Salvatore Petralia, Luca Lanzanò, Giuseppe Broggi and Massimo Camarda

Cancers 2022, 14(1), 198; https://doi.org/10.3390/cancers14010198 - 31 Dec 2021

Cited by 33 | Viewed by 3450

Abstract

Liquid biopsy is emerging as a potential diagnostic tool for prostate cancer (PC) prognosis and diagnosis. Unfortunately, most circulating tumor cells (CTC) technologies, such as AdnaTest or Cellsearch^®, critically rely on the epithelial cell adhesion molecule (EpCAM) marker, limiting the possibility [...] Read more.

Liquid biopsy is emerging as a potential diagnostic tool for prostate cancer (PC) prognosis and diagnosis. Unfortunately, most circulating tumor cells (CTC) technologies, such as AdnaTest or Cellsearch^®, critically rely on the epithelial cell adhesion molecule (EpCAM) marker, limiting the possibility of detecting cancer stem-like cells (CSCs) and mesenchymal-like cells (EMT-CTCs) that are present during PC progression. In this context, dielectrophoresis (DEP) is an epCAM independent, label-free enrichment system that separates rare cells simply on the basis of their specific electrical properties. As compared to other technologies, DEP may represent a superior technique in terms of running costs, cell yield and specificity. However, because of its higher complexity, it still requires further technical as well as clinical development. DEP can be improved by the use of microfluid, nanostructured materials and fluoro-imaging to increase its potential applications. In the context of cancer, the usefulness of DEP lies in its capacity to detect CTCs in the bloodstream in their epithelial, mesenchymal, or epithelial–mesenchymal phenotype forms, which should be taken into account when choosing CTC enrichment and analysis methods for PC prognosis and diagnosis. Full article

(This article belongs to the Special Issue Bio-Pathological Markers for the Diagnosis and Therapy of Cancers, Volume II)

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