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Molecular Determinants of Prostate Cancer Metastasis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 18382

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Special Issue Editor

Dr. Josiah Ochieng

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Guest Editor

Meharry Medical College, Nashville, TN 37208, USA
Interests: molecular; determinants; cancer metastasis; fetuin-A; galectin-3; prostate cancer; breast cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

The metastatic process in prostate cancer (PCa), just like in other malignancies, is indeed complex, involving numerous signaling molecules. To complicate matters, stromal cells in the tumor microenvironment also participate actively in the process. For the last 30 years or more, key proteins that were thought to be part of a unifying theme in the process such as matrix metalloproteinase have been defined. However, despite the intense global efforts to design effective inhibitors for these enzymes to combat metastasis, little was accomplished. Prostate cancer, however, unlike other tumors such as pancreatic cancer, grows more slowly and can be divided into indolent and aggressive subtypes. The aggressive subtypes arising from prostate cancer stem cells are normally unresponsive to hormonal therapy. These have the propensity to grow rapidly and metastasize. Therefore, there is an urgent need to uncover the unifying process or processes that provide metastatic advantage to the aggressive subtypes of PCa.

Dr. Josiah Ochieng
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

prostate
stem
aggressive
indolent
metastasis
hormonal
therapy
stromal
microenvironment
subtype

Published Papers (6 papers)

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Research

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17 pages, 1869 KiB

Open AccessArticle

SPARC Induces E-Cadherin Repression and Enhances Cell Migration through Integrin αvβ3 and the Transcription Factor ZEB1 in Prostate Cancer Cells

by Fernanda López-Moncada, María José Torres, Boris Lavanderos, Oscar Cerda, Enrique A. Castellón and Héctor R. Contreras

Int. J. Mol. Sci. 2022, 23(11), 5874; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23115874 - 24 May 2022

Cited by 8 | Viewed by 2258

Abstract

Secreted protein acidic and rich in cysteine (SPARC), or osteonectin, is a matricellular protein that modulates interactions between cells and their microenvironment. SPARC is expressed during extracellular matrix remodeling and is abundant in bone marrow and high-grade prostate cancer (PCa). In PCa, SPARC induces changes associated with epithelial–mesenchymal transition (EMT), enhancing migration and invasion and increasing the expression of EMT transcriptional factor Zinc finger E-box-binding homeobox 1 (ZEB1), but not Zinc finger protein SNAI1 (Snail) or Zinc finger protein SNAI2 (Slug). It is unknown whether the SPARC-induced downregulation of E-cadherin in PCa cells depends on ZEB1. Several integrins are mediators of SPARC effects in cancer cells. Because integrin signaling can induce EMT programs, we hypothesize that SPARC induces E-cadherin repression through the activation of integrins and ZEB1. Through stable knockdown and the overexpression of SPARC in PCa cells, we demonstrate that SPARC downregulates E-cadherin and increases vimentin, ZEB1, and integrin β3 expression. Knocking down SPARC in PCa cells decreases the tyrosine-925 phosphorylation of FAK and impairs focal adhesion formation. Blocking integrin αvβ3 and silencing ZEB1 revert both the SPARC-induced downregulation of E-cadherin and cell migration enhancement. We conclude that SPARC induces E-cadherin repression and enhances PCa cell migration through the integrin αvβ3/ZEB1 signaling pathway. Full article

(This article belongs to the Special Issue Molecular Determinants of Prostate Cancer Metastasis)

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17 pages, 2703 KiB

Open AccessArticle

High eEF1A1 Protein Levels Mark Aggressive Prostate Cancers and the In Vitro Targeting of eEF1A1 Reveals the eEF1A1–actin Complex as a New Potential Target for Therapy

by Alessandra Bosutti, Barbara Dapas, Gabriele Grassi, Rossana Bussani, Fabrizio Zanconati, Fabiola Giudici, Cristina Bottin, Nicola Pavan, Carlo Trombetta and Bruna Scaggiante

Int. J. Mol. Sci. 2022, 23(8), 4143; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084143 - 08 Apr 2022

Cited by 3 | Viewed by 1848

Abstract

Although the eukaryotic elongation factor eEF1A1 plays a role in various tumours, there is little information on its prognosis/therapeutic value in prostate carcinoma. In high-grade and castration-resistant prostate carcinoma (CRPC), the identification of novel therapeutic markers/targets remains a priority. The expression of eEF1A1 protein was determined in formalin-fixed, paraffin-embedded prostate cancer and hyperplasia tissue by IHC. The role of eEF1A1 was investigated in a cellular model using a DNA aptamer (GT75) we previously developed. We used the aggressive CRPC cancer PC-3 and non-tumourigenic PZHPV-7 lines. Cytotoxicity was measured by the MTS assay and eEF1A1 protein levels by in-cell Western assays. The mRNA levels of eEF1A1 were measured by qPCR and ddPCR. Higher expression of eEF1A1 was found in Gleason 7–8 compared with 4–6 tissues (Gleason ≥ 7, 87% versus Gleason ≤ 6, 54%; p = 0.033). Patients with a high expression of eEF1A1 had a worse clinical outcome. In PC-3, but not in PZHPV-7, GT75 decreased cell viability and increased autophagy and cell detachment. In PC-3 cells, but not in PZHPV-7, GT75 mainly co-localised with the fraction of eEF1A1 bound to actin. Overexpression of the eEF1A1 protein can identify aggressive forms of prostate cancer. The targeting of eEF1A1 by GT75 impaired cell viability in PC-3 cancer cells but not in PZHPV-7 non-tumourigenic cells, indicating a specific role for the protein in cancer survival. The eEF1A1–actin complexes appear to be critical for the viability of PC-3 cancer cells, suggesting that eEF1A1 may be an attractive target for therapeutic strategies in advanced forms of prostate cancer. Full article

(This article belongs to the Special Issue Molecular Determinants of Prostate Cancer Metastasis)

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15 pages, 2725 KiB

Open AccessArticle

Fetuin-A Promotes 3-Dimensional Growth in LNCaP Prostate Cancer Cells by Sequestering Extracellular Vesicles to Their Surfaces to Act as Signaling Platforms

by Josiah Ochieng, Olga Y. Korolkova, Guoliang Li, Renjie Jin, Zhenbang Chen, Robert J. Matusik, Samuel Adunyah, Amos M. Sakwe and Olugbemiga Ogunkua

Int. J. Mol. Sci. 2022, 23(7), 4031; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23074031 - 05 Apr 2022

Cited by 5 | Viewed by 1825

Abstract

The present studies were conducted to evaluate key serum proteins and other components that mediate anchorage-independent growth (3-D growth) of LNCaP prostate cancer cells as spheroids. The cells were cultured on ultra-low attachment plates in the absence and presence of fetuin-A and with or without extracellular vesicles. The data show that fetuin-A (alpha 2HS glycoprotein) is the serum protein that mediates 3-D growth in these cells. It does so by sequestering extracellular vesicles of various sizes on the surfaces of rounded cells that grow as spheroids. These vesicles in turn transmit growth signals such as the activation of AKT and MAP kinases in a pattern that differs from the activation of these key growth signaling pathways in adherent and spread cells growing in 2-D. In the process of orchestrating the movement and disposition of extracellular vesicles on these cells, fetuin-A is readily internalized in adhered and spread cells but remains on the surfaces of non-adherent cells. Taken together, our studies suggest the presence of distinct signaling domains or scaffolding platforms on the surfaces of prostate tumor cells growing in 3-D compared to 2-D. Full article

(This article belongs to the Special Issue Molecular Determinants of Prostate Cancer Metastasis)

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22 pages, 5283 KiB

Open AccessArticle

Exosomal miRNAs from Prostate Cancer Impair Osteoblast Function in Mice

by Giulia Furesi, Antonio Miguel de Jesus Domingues, Dimitra Alexopoulou, Andreas Dahl, Matthias Hackl, Johannes R. Schmidt, Stefan Kalkhof, Thomas Kurth, Hanna Taipaleenmäki, Stefanie Conrad, Christine Hofbauer, Martina Rauner and Lorenz C. Hofbauer

Int. J. Mol. Sci. 2022, 23(3), 1285; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031285 - 24 Jan 2022

Cited by 16 | Viewed by 3556

Abstract

Prostate cancer (PCa) is the most frequent malignancy in older men with a high propensity for bone metastases. Characteristically, PCa causes osteosclerotic lesions as a result of disrupted bone remodeling. Extracellular vesicles (EVs) participate in PCa progression by conditioning the pre-metastatic niche. However, how EVs mediate the cross-talk between PCa cells and osteoprogenitors in the bone microenvironment remains poorly understood. We found that EVs derived from murine PCa cell line RM1-BM increased metabolic activity, vitality, and cell proliferation of osteoblast precursors by >60%, while significantly impairing mineral deposition (−37%). The latter was further confirmed in two complementary in vivo models of ossification. Accordingly, gene and protein set enrichments of osteoprogenitors exposed to EVs displayed significant downregulation of osteogenic markers and upregulation of proinflammatory factors. Additionally, transcriptomic profiling of PCa-EVs revealed the abundance of three microRNAs, miR-26a-5p, miR-27a-3p, and miR-30e-5p involved in the suppression of BMP-2-induced osteogenesis in vivo, suggesting the critical role of these EV-derived miRNAs in PCa-mediated suppression of osteoblast activity. Taken together, our results indicate the importance of EV cargo in cancer-bone cross-talk in vitro and in vivo and suggest that exosomal miRNAs may contribute to the onset of osteosclerotic bone lesions in PCa. Full article

(This article belongs to the Special Issue Molecular Determinants of Prostate Cancer Metastasis)

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Review

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15 pages, 1076 KiB

Open AccessReview

The Expression of Proto-Oncogene ETS-Related Gene (ERG) Plays a Central Role in the Oncogenic Mechanism Involved in the Development and Progression of Prostate Cancer

by Ealia Khosh Kish, Muhammad Choudhry, Yaser Gamallat, Sabrina Marsha Buharideen, Dhananjaya D and Tarek A. Bismar

Int. J. Mol. Sci. 2022, 23(9), 4772; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094772 - 26 Apr 2022

Cited by 19 | Viewed by 3931

Abstract

The ETS-related gene (ERG) is proto-oncogene that is classified as a member of the ETS transcription factor family, which has been found to be consistently overexpressed in about half of the patients with clinically significant prostate cancer (PCa). The overexpression of ERG can mostly be attributed to the fusion of the ERG and transmembrane serine protease 2 (TMPRSS2) genes, and this fusion is estimated to represent about 85% of all gene fusions observed in prostate cancer. Clinically, individuals with ERG gene fusion are mostly documented to have advanced tumor stages, increased mortality, and higher rates of metastasis in non-surgical cohorts. In the current review, we elucidate ERG’s molecular interaction with downstream genes and the pathways associated with PCa. Studies have documented that ERG plays a central role in PCa progression due to its ability to enhance tumor growth by promoting inflammatory and angiogenic responses. ERG has also been implicated in the epithelial–mesenchymal transition (EMT) in PCa cells, which increases the ability of cancer cells to metastasize. In vivo, research has demonstrated that higher levels of ERG expression are involved with nuclear pleomorphism that prompts hyperplasia and the loss of cell polarity. Full article

(This article belongs to the Special Issue Molecular Determinants of Prostate Cancer Metastasis)

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11 pages, 565 KiB

Open AccessReview

AR-V7 in Metastatic Prostate Cancer: A Strategy beyond Redemption

by Navid Sobhani, Praveen Kumar Neeli, Alberto D’Angelo, Matteo Pittacolo, Marianna Sirico, Ilaria Camilla Galli, Giandomenico Roviello and Gabriella Nesi

Int. J. Mol. Sci. 2021, 22(11), 5515; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115515 - 24 May 2021

Cited by 19 | Viewed by 4263

Abstract

Metastatic prostate cancer is the most common cancer in males and the fifth cause of cancer mortality worldwide. Despite the major progress in this field, leading to the approval of novel anti-androgens, the prognosis is still poor. A significant number of patients acquire an androgen receptor splice variant 7 (AR-V7), which is constitutively activated and lacks the ligand-binding domain (LBD) while maintaining the nuclear localization signal and DNA-binding domain (DBD). This conformational change, even in the absence of the ligand, allows its retention within the nucleus, where it acts as a transcription factor repressing crucial tumor suppressor genes. AR-V7 is an important oncogenic driver and plays a role as an early diagnostic and prognostic marker, as well as a therapeutic target for antagonists such as niclosamide and TAS3681. Anti-AR-V7 drugs have shown promise in recent clinical investigations on this subset of patients. This mini-review focuses on the relevance of AR-V7 in the clinical manifestations of castration-resistant prostate cancer (CRPC) and summarizes redemptive therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Determinants of Prostate Cancer Metastasis)

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