Expression and regulation of aldehyde dehydrogenases in prostate cancer

The functional role of aldehyde dehydrogenases(ALDHs)in prostate cancer remains an area of some controversy.Many studies have used high ALDH functional activity to isolate putative cancer stem cells with tumour-initiating and propagating properties,while evidence is also emerging about the involvement of specific isoforms in migration,invasiveness and metastasis.Identification of specific ALDH isoforms,which contribute to both drug resistance and aggressiveness of the disease remains a challenge within the complex heterogeneity of prostate cancer.The purpose of this perspective is to dissect functional roles for ALDH in the tumour microenvironment and to evaluate the potential of the ALDH gene family as biomarkers and/or targets for therapeutic intervention.

Introduction of the special issue “How does the prostate cancer microenvironment affect the metastatic process and/or treatment outcome?”

It is with great pleasure that we introduce this special issue titled“How does the prostate cancer microenvironment affect the metastatic process and/or treatment outcome?”.Within this issue we,and our fellow authors,explore the role of the prostate cancer microenvironment in tumour metastasis and treatment outcome.Global statistics reveal that prostate cancer is the second most common form of cancer and is attributable to fifth of all cancer-related deaths to affect men worldwide.Whilst rates of disease incidence appear to be increasing a high proportion of men diagnosed with disease will survive for ten or more years.

The role of MT1-MMP in the progression and metastasis of osteosarcoma

The dysregulation of Membrane-type 1 matrix metalloproteinase(MT1-MMP)has been extensively studied in numerous cancer types,and plays key roles in angiogenesis,cancer progression,and metastasis.MT1-MMP is a predictor of poor prognosis in osteosarcoma(OS),yet the molecular mechanisms of disease progression are unclear.This review provides a summary of the literature relating to the gene and protein expression of MT1-MMP(MMP-14)in OS clinical samples,evaluates the expression in cell lines and experimental models,and analyses its potential role in the progression and metastasis of OS.In addition,the therapeutic potential of MT1-MMP as a drug target has been assessed.Due to the biological complexity of MMPs,inhibition has proven to be challenging.However,exploiting the expression and proteolytic capacity of MT1-MMP could open new avenues in the search for novel,safer and selective drugs for use in OS.

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Androgens play an important role in prostate cancer(PCa)development and progression.Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer,patients eventually relapse with the lethal form of the disease.The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor(AR).Inhibiting the steroidogenic enzymes that play vital roles in the biosynthesis of testosterone(T)and dihydrotestosterone(DHT)seems to be an attractive strategy for PCa therapies.Emerging data suggest a role for the enzymes mediating pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels,and thereby influencing PCa progression.This supports the idea for the development of multi-targeting strategies,involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis.In this review,we will focus on CYP17A1,AKR1C3,HSD17B3 and SRD5A,as these enzymes play essential roles in all the three androgenic pathways.We will review also the AR as an additional target for the design of bifunctional drugs.Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.

Membrane-type matrix metalloproteinases: expression, roles in metastatic prostate cancer progression and opportunities for drug targeting

The membrane-type matrix metalloproteinases(MT-MMPs),an important subgroup of the wider MMP family,demonstrate widespread expression in multiple tumor types,and play key roles in cancer growth,migration,invasion and metastasis.Despite a large body of published research,relatively little information exists regarding evidence for MT-MMP expression and function in metastatic prostate cancer.This review provides an appraisal of the literature describing gene and protein expression in prostate cancer cells and clinical tissue,summarises the evidence for roles in prostate cancer progression,and examines the data relating to MT-MMP function in the development of bone metastases.Finally,the therapeutic potential of targeting MT-MMPs is considered.While MT-MMP inhibition presents a significant challenge,utilisation of MT-MMP expression and proteolytic capacity in prostate tumors is an attractive drug development opportunity.

Current challenges and opportunities in treating hypoxic prostate tumors

Hypoxia is a well-established characteristic of prostate tumors and is now recognised as a major contributory factor to both tumor progression and increased resistance to therapy.One strategy to target hypoxic tumor cells is the development of hypoxia-activated prodrugs(HAPs),which are activated in low oxygen environments.Several HAPs have been developed but despite encouraging results from preclinical studies many of these have performed disappointingly in clinical trials.In the developing era of precision medicine,it is clear that more strategic deployment of these agents is required,based on reliable methods that can identify patients who will benefit from HAP treatment,either alone or in combination with other drugs.This review discusses the primary limitations of using HAPs to treat hypoxic tumors and explains how these challenges can be addressed.In particular,it emphasises the importance of tumor imaging and identification of reliable biomarkers for measuring hypoxia and monitoring cellular response to treatment in individual patients.Developing predictive assays for clinical use will be paramount in demonstrating the patient impact and effectiveness of HAPs for personalised medicine.

HOX transcription factors and the prostate tumor microenvironment

It is now well established that the tumor microenvironment plays an essential role in the survival,growth,invasion,and spread of cancer through the regulation of angiogenesis and localized immune responses.This review examines the role of the HOX genes,which encode a family of homeodomain-containing transcription factors,in the interaction between prostate tumors and their microenvironment.Previous studies have established that HOX genes have an important function in prostate cancer cell survival in vitro and in vivo,but there is also evidence that HOX proteins regulate the expression of genes in the cancer cell that influence the tumor microenvironment,and that cells in the microenvironment likewise express HOX genes that confer a tumor-supportive function.Here we provide an overview of these studies that,taken together,indicate that the HOX genes help mediate cross talk between prostate tumors and their microenvironment.