The Journal of Pathology

Cover image for Vol. 234 Issue 3

Edited By: Peter A Hall, Editor-in-Chief

Impact Factor: 7.33

ISI Journal Citation Reports © Ranking: 2013: 3/76 (Pathology); 15/202 (Oncology)

Online ISSN: 1096-9896

Associated Title(s): The Journal of Pathology: Clinical Research

Virtual Issues


Welcome to The Journal of Pathology's Virtual Issues page

List of issues

2013 Issue 3, August: Next generation sequencing in pathology
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2013 Issue 2, May: Progress in prostate cancer
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2013 Issue 1, February: The microenvironment and cancer
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2012 Issue 4, December: Animal Models of Disease
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2012 Issue 3, August: Getting your papers published: A view from The Journal of Pathology Editorial team
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2012 Issue 2, March: Stem cells, clonal expansion and cancer progression
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2012 Issue 1, February: Recent advances in our understanding of gynaecological pathology
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2011 Issue 4, November: Progress in our understanding of the pathobiology of hypoxia and angiogenesis
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2011 Issue 3, August: The molecular pathology of sarcomas
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2011 Issue 2, April: Recent advances in the molecular pathology of micro-RNAs
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2011 Issue 1, February: Neuropathology: Advances in technology and biology
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2010 Issue 4, December: Recent advances in the pathobiology of lymphoma
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2010 Issue 3, September: Recent advances in renal pathology
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2010 Issue 2, June: Recent advances in breast cancer
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2010 Issue 1, April: p53: Recent advances in our understanding of this key tumour suppressor
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The Journal of Pathology 2013 Virtual Issue Number 3, August


Next generation sequencing in pathology

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Compiled and annotated by David T. Bonthron, Senior Editor at the Journal of Pathology and Professor of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds, LS9 7TF, UK

"Next-generation sequencing" is one of those phrases that really should have quickly disappeared from use -- the massively parallel technologies to which it refers are now the staple diet of biomedical science. A new instrument bringing further incremental improvement lies around each corner. Hardly "next generation" - not anymore...

Maybe then, the persistence of this forward-looking jargon term tells us something about the impact of these technologies on the scientific process. Nowadays, in genetic and dependent disciplines, data acquisition is cheap and easy. Much more of the scientific challenge consists of analysis and interpretation, and because these depend heavily on computational methods, there has been a huge shift in the core skill-sets needed in biomedical research. Perhaps for the first time in the history of biology, many senior investigators find themselves lacking the scientific skills required to plan and direct research from an informed position. Like music or chess, the fundamentals underpinning modern bioinformatics are not best learnt in middle age. The real "next generation", then, is the human one, the young scientists driving the implementation of new methods of enquiry. They have assumed centre stage.

There is insufficient space here to attempt to summarize all the diverse ways in which NGS can be applied in biomedical research and diagnostics. It has notable capabilities, though, that deserve brief mention. It can be exquisitely sensitive; the resequencing of a known mutation target at high read depth can allow detection of mutations at levels of mosaicism far below the detection limits of conventional sequencing methods, and which would formerly have required laborious cloning methods. It is readily quantifiable; read numbers matching a given genomic or transcript target can thus be interpreted in terms of copy number or expression level. Finally, for diagnostic pathologists, the huge capacity of NGS can be harnessed for parallel analysis of multiple genes in multiple subjects, simultaneously broadening diagnostic coverage and reducing costs.

In this virtual issue, we highlight a range of studies that exploit the power of NGS in the study of human disease. Most of them focus on cancer, entirely unsurprising given its immense importance and largely genetic causation. Even a brief review of these impressive studies make it clear that our knowledge of cancer genomics already greatly exceeds our understanding. Should we question the value of cancer genomics, then? In their overview of this area, Taylor and Ladanyi [1] offer us many reminders of why we should resist becoming cynical. Genomic abberations that drive tumorigenesis, once they are tested out from the bewildering complexity of tumour genetics, have repeatedly led to the identification of key therapeutic targets.

 1 Clinical cancer genomics: how soon is now?
Taylor B.S. and Ladanyi M.et al.
The Journal of Pathology 2011; 223: 318-326
Tumour pathogenesis

Prostate cancer, more than most, has been illuminated by recent large-scale genomic analyses. Weier et al. [2] used discrepant mapping of the paired-end reads of individual genomic fragments to characterise the TMPRSS2-ERG translocation breakpoints in 25 of 83 prostate cancers, as well as less frequent translocations involving other genes. The clustering of these breakpoints at hotspots of androgen-induced chromosome breakage is consistent with models that invoke androgen-driven genome rearrangement as an important tumorigenic mechanism.

In a series of 6 prostate cancers lacking TMPRSS2-ERG fusions, Lapuk et al. [3] combined genome and transcriptome analysis to reveal a high frequency of novel fusion genes as well as characteristic patterns of gene expression. Strikingly, they were able to discern prostate-cancer-specific patterns even within histologically normal lymph node, suggesting the presence of undiagnosed occult metastatic disease.

Wu et al. [4] performed genome and transcriptome sequencing of an aggressive prostate cancer in a young subject, identifying 15 tumour-specific translocations that were common to primary and metastatic disease, but private and not reported in other prostate cancers. The identities of the genes involved in the rearrangements could be related directly to the intermediate gene expression patterns displayed by this unusual tumour, with both androgen-related and neuroendocrine characteristics.

 2 Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer
Weier C, Haffner MC, Mosbruger T, et al.
The Journal of Pathology 2013; 230: 174-183
 3 From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer
Lapuk A.V., Wu C., Wyatt A.W., et al.
The Journal of Pathology 2012; 227: 286-297.
 4

Integrated genome and transcriptome sequencing identifies a novel form of hybrid and aggressive prostate cancer
Wu C, Wyatt AW, Lapuk A.V., et al.
The Journal of Pathology 2012; 227: 53-61

Moving to breast cancer, Natrajan et al. [5] compared the genome sequences of ER+ and ER- tumours from germline BRCA1 mutation carriers, to try to resolve controversy about the relationship between BRCA1 mutation status and development of ER+ tumours. SImilar patterns of genetic aberrations (consistent with loss of homologous recombination DNA repair), together with loss of the wild-type BRCA1 allele, were seen in each case, arguing in favour of a true pathogenic status for the germ line BRCA1 mutation, even in ER+ tumours.

Mucosal melanoma is an uncommon tumour with a poor prognosis. Furney et al. [6] performed whole genome and whole exome sequencing to show that mucosal melanomas have far fewer (~70) non-synonymous exon mutations than sun-exposed cutaneous melanomas (~300-400). This, together with their four-fold higher rate of structural genomic aberrations, clearly indicates distinct genetic mechanisms driving the development of these two tumour types.

RNA-level analysis is also a powerful way to identify genomic aberrations that drive tumour development. Majewski et al. [7] used targeted enrichment of kinase transcripts to identify rearrangements fusing FGFR3 and ALK to other genes in non-small-cell lung cancer. Their findings underscore the extreme heterogeneity of genomic rearrangements in lung cancer, as well as intriguing overlaps with other tumour types such as bladder cancer, in which the same type of FGFR3 rearrangements and point mutations are seen.

 5 A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers
Natrajan R., Mackay A., Lambros M.B., et al.
The Journal of Pathology 2012; 227: 29-41

 6 Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma
Furney S.J., Turajlic S., Stamp G., et al.
The Journal of Pathology 2013; 230: 261-269.

 7

Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centered RNA sequencing
Majewski I.J., Mittempergher L., Davidson N.M., et al.
The Journal of Pathology 2013; 230: 270–276

Tumour evolution

NGS also offers powerful ways to observe the processes of tumour evolution and response to treatment, by comparison of the genomic architecture and transcription patterns of primary and metastatic lesions at different times. Castellarin et al. [8] used whole exome sequencing to study somatic mutations in primary ovarian tumours and ascites fluid at recurrence. Most primary tumour mutations were still present at recurrence, indicating a failure of chemotherapy to eliminate many primary tumour clones. In contrast, Kasaian et al. [9] employed whole-genome and transcriptome sequencing to compare the genomes of a primary and recurrent parathyroid carcinoma (PTC). This revealed not only a novel spectrum of somatic point mutations, but tumour-specific rearrangements. Such intensive scrutiny of individual cases appears to be the best way to obtain the maximum amount of information on the pathogenesis of rare tumour types such as PTC.

 8 Clonal evolution of high-grade serous ovarian carcinoma from primary to recurrent disease
Castellarin M., Milne K., Zeng T., et al.
The Journal of Pathology 2013; 229: 515-524
 9 Complete genomic landscape of a recurring sporadic parathyroid carcinoma
Kasaian K., Wiseman S.M., Thiessen N., et al.
The Journal of Pathology 2013; 230: 249–260.

Tumour classification

With its ability to analyse multiple genes simultaneously, NGS has the potential in a diagnostic setting to complement or even replace older methods of disease classification, such as those based on histology or immunohistochemistry. The classification of gynaecological tumour is the subject of much attention using these new methods. McConechy et al. [10] demonstrate characteristic differences between subtypes of endometrial carcinoma, in their profiles of mutations within a panel of nine genes.Subsequent identification of outlying cases with apparently discrepant mutational and morphological classification enabled the reclassification of a number of cases that had borderline histology

Jones et al. [11] performed whole exome sequencing of enriched tumour cell populations from low-grade serous ovarian cancers, finding that very few somatic point mutations occur in this tumour type, aside from those in wither BRAF or KRAS. Despite the low mutational yield of this study, it carries the highly significant message that the KRAS-BRAF-MEK-MAPK pathway should be investigated as a therapeutic target in this subgroup of ovarian cancers. McBride et al. [12] characterised genomic rearrangements in ovarian cancers using paired-end genomic sequencing. A subset of high-grade serous tumours displayed a high frequency of tandem duplications, a molecular phenotype shared with triple-negative breast cancers.

 10 Use of mutation profiles to refine the classification of endometrial carcinomas
McConechy M.K., Ding J., Cheang M.C.U., et al.
The Journal of Pathology 2012; 228: 20-30
 11 Low-grade serous carcinomas of the ovary contain very few point mutations
Jones S., Wang T.L., Kurman R.J., et al.
The Journal of Pathology 2012; 226: 413-420.

 12

Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes
McBride D.J., Etemadmoghadam D. Cooke S.L., et al.
The Journal of Pathology 2012; 227: 446-455

NGS in the elucidation of gene regulatory networks

ChIP-seq (chromatin immunoprecipitation followed by NGS) is a powerful method for directly defining the genomic targets of transcriptional regulators. By determining which DNA sequences are enriched in chromatin immunoprecipitates, target genes and consensus DNA binding sites can be elucidated. Nelson et al. [13] used a combination of transcriptional profiling and ChIP-seq to show that the hallmark chordoma oncogene T (brachyury) up-regulates a network of genes including a large subset of those involved in cell cycle control.

 13 An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma
Nelson A.C., Pillay N., Henderson S., et al. The Journal of Pathology 2012; 228: 274-285
Non-invasive diagnosis

Human plasma normally contains minute quantities of highly fragmented cell-free DNA. In pregnancy, a proportion of this is fetal, and in cancer patients, some is tumour-derived. Lo and Chiu [14] review the diverse ways in which NGS technology now allows access to this DNA for diagnostic purposes, permitting applications as different as prenatal diagnosis of chromosomal abnormalities and monitoring of remission samples for the re-appearance of a tumour-specific genetic marker.

 14 Plasma nucleic acid analysis by massively parallel sequencing: pathological insights and diagnostic implications
Lo Y.M. and Chiu R.W.K.
The Journal of Pathology 2011; 225: 318-323
Infection, epidemiology and disease history

Finally to infection, still untoppled as the biggest killer of all. Compared to the challenges of analyzing the large repetitive genomes that vertebrates are endowed with, NGS has made the task of de novo sequencing and assembly of microbial genomes trivial. Viruses, too, can be sub-classified and their evolution followed much more precisely on the basis of their sequences than by immunological criteria. The advent of NGS has also completely changed what is possible in the field of pathogen detection. Xiao et al. [15] provide a powerful demonstration of how they could reassemble the 1918 influenza pandemic virus in a few days, using formalin-fixed tissue nearly a century old. Remarkably, in this RNA-based sequencing study, they were also even able to deduce aspects of the pattern of host defence, based on gene expression analysis.

The memory of disease battles, long since fought and lost, lives on in a multitude of preserved tissue samples around the world.The new lessons that modern sequencing technology are empowering us to learn are remarkable indeed. The "next generation" -- of humans, that is, not sequencing machines -- will benefit from biomedical knowledge on a scale unimaginable evena short while ago.

 15 High-throughput RNA sequencing of a formalin-fixed, paraffin-embedded autopsy lung tissue sample from the 1918 influenza pandemic
Xiao Y.L., Kash J.C., Beres S.B., et al.
The Journal of Pathology 2013; 229: 535-545

Questions

The following questions can be answered by reading, and reflecting upon, the above annotation and the papers that are cited within it. Within the Royal College of Pathologists Continuing Professional Development (CPD) scheme, CPD points may be earned by writing reflective notes on the papers in this Virtual Issue and the questions are designed to act as a focus for this activity. To do this, you may wish to use the Royal College of Pathologists' reflective notes form.

 Question 1 What are the differences between a human genome, an "exome" and a "transcriptome"? What are their relative sizes? For what purposes might each of these be the analytical target of choice?

 Question 2 Large-scale genomic abnormalities (copy-number variations and translocations) are common and diverse in tumours. What type of NGS experimental designs would be required to detect (a) copy number variations at high resolutions and (b) balanced translocations?

 Question 3 What are the key advantages offered by NGS methods in the analysis of archival pathological material? WHich other genomic analysis methods cannot be applied to such material, and why?


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The Journal of Pathology 2013 Virtual Issue Number 2, May


Progress in prostate cancer

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Compiled and annotated by Daniel M. Berney, Department of Molecular Pathology, Barts Cancer Institute, Queen Mary University of London, UK

Prostate cancer remains a major challenge for both diagnostic and experimental pathologists. It is one of the commonest cancers, yet we know less about its pathogenesis than most other common malignancies. It is a significant cause or mortality and morbidity in the Western world, yet most cases, especially those detected by screening, do not progress and patients usually die with their prostate cancer rather than from it. The search for biomarkers associated with prostate cancer aggressive behaviour has been accelerated by investigation of prostate cancer pathogenesis and genetics. The discovery of potential clinical targets has also accelerated in the past few years and the treatment options for both early and advanced prostate cancer seems to change on a yearly basis. The Journal of Pathology has been in the forefront of this search, with many papers exploring mechanistic and more clinically associated areas of the disease.

The genetics of prostate cancer

The most striking genetic finding in prostate cancer has been the high frequency of TMPRSS2-ERG rearrangements that occur in 50% of prostate cancers. Weier et al. [1] investigated the genomic architecture of these rearrangements using next generation sequencing to examine rearrangement breakpoints in the fusion gene in 83 primary prostate cancers. They show that the rearrangement breakpoints show strong clustering in specific intronic regions of TMPRSS2 and ERG and 88% occurred at or near regions of microhomology or involved insertions of one or more base pairs showing the specific nature of these re-arrangements. A number of studies have shown the existence of genetic regions which predispose for prostate cancer. Helfand et al. [2] demonstrate that chromosomal regions associated with prostate cancer susceptibility are preferentially localized to lamin B-deficient microdomains (LDMDs). LDMD frequency is correlated with prostate cancer cell line aggessiveness and increased cell motility. Furthermore, LDMDs were observed in human prostate cancer tissue and their frequency was correlated with increased Gleason grade. Nuclear morphological changes are a key feature of neoplasia and it perhaps extraordinary that we understand so little of the mechanisms that determine this.

The ability to perform increasingly detailed genetic analysis of cancers is demonstrated by Lapuk et al. [3]. They performed massive parallel sequencing, performing deep RNA and shallow DNA sequencing in 6 primary tumours. They massively expanded on the number of novel fusion genes known, linked fusion gene aetiology and gene expression profiles and showed the utility of fusion genes for molecular pathology by implicating the RE1-Silencing Transcription factor (REST) in the development of neuroendocrine prostatic cancers. A second paper from the same group [4] used next-generation sequencing on a single aggressive prostate adenocarcinoma using primary and metastatic tissues. They identified the area of primary cancer most likely to give rise to the metastasis and hypothesized that the amplification and over-expression of the stem cell gene MSI2 may have contributed to a hybrid luminal-neuroendocrine tumour of aggressive type. Lehmusvaara et al. [5] examined the molecular mechanisms of hormonal therapy by comparing the effects genetic effects of therapy with a control group in 28 men where frozen specimens were used for gene expression profiling for all known protein-coding genes. They show the significantly different effects of an anti-androgen and a GnRH agonist on gene expression. Also TMPRSS2-ERG fusion seems to bring many proliferation-related genes under androgen regulation.

 1 Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer
Weier C, Haffner MC, Mosbruger T, et al. The Journal of Pathology 2013; Accepted manuscript online. DOI:10.1002/path.4186
The Journal of Pathology 2013; Accepted manuscript online. DOI:10.1002/path.4186

 2 Chromosomal regions associated with prostate cancer risk localize to lamin B-deficient microdomains and exhibit reduced gene transcription
Helfand BT, Wang Y, Pfleghaar K, et al.
The Journal of Pathology 2012; 226: 735–745.

 3

From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer
Lapuk AV, Wu C, Wyatt AW, et al.
The Journal of Pathology 2012; 227: 286–297

 4 Integrated genome and transcriptome sequencing identifies a novel form of hybrid and aggressive prostate cancer
Wu C, Wyatt AW, Lapuk AV, et al.
The Journal of Pathology 2012; 227: 53–61

 5 Chemical castration and anti-androgens induce differential gene expression in prostate cancer
Lehmusvaara S, Erkkilä T, Urbanucci A, et al.
The Journal of Pathology 2012; 227:336–345.

In vitro studies

Metallothioneins (MT) are a group of metal binding proteins thought to play a role in the detoxification of heavy metals. Han et al. [6] show that MT1h, a metallothienin, demonstrates, in culture and xenografts, that MT1h demonstrates tumor suppressor activity that is dependent on activation of histone methylation. Prostatic squamous metaplasia is seen in response to oestrogen and oestrogen receptor Chen et al. [7] used a mouse model that has selectively lost ERα in either stromal or epithelial prostate cells to determine the requirements of ERα for oestrogen-stimulated prostate proliferation. They suggest that epithelial ERα is required for oestrogen-mediated proliferative response and could be an appropriate target for preventing aberrant oestrogen signalling in the prostate. The PMEPA1 gene has been shown to suppress the androgen receptor (AR) and TGFβ signalling pathways and is abnormally expressed in prostate tumours. Liu et al. [8] demonstrate that inhibition of PMEPA1 suppresses AR-negative cell lines through up-regulating p21 transcription. PMEPA1 may promote AR-negative prostate cancer cell proliferation through p21 and this may be a potential target for future therapies.

 6 Metallothionein 1h tumor suppressor activity in prostate cancer is mediated by euchromatin methyltransferase
Han Y-C, Zheng Z-L, Zuo Z-H, et al.
The Journal of Pathology 2013; Accepted manuscript online. DOI: 10.1002/path.4169

 7 Loss of epithelial oestrogen receptor α inhibits oestrogen-stimulated prostate proliferation and squamous metaplasia via in vivo tissue selective knockout models
Chen M, Yeh C-R, Chang H-C, et al.
The Journal of Pathology 2012; 226:17–27.

 8

PMEPA1 promotes androgen receptor-negative prostate cell proliferation through suppressing 3 the Smad3/4–c-Myc–p21 signaling pathway
Liu R, Zhou Z, Huang J and Chen C.
The Journal of Pathology 2011; 223:683–694.

Stem cells in the prostate

Until recently, our knowledge of stem cells in the prostate have been rudimentary. Two recent papers in Journal of Pathology have illuminated this area. Knowledge of stem cells is vital to understand cancer pathogenesis and also potentially for future clinical drug targets to the progenitor cells. Blackwood et al. [9] use mitochondrial DNA (mtDNA) mutations to map stem cell fate. The clonal relationships within the human prostate epithelial cell layers were explored by this method. They suggests that individual acini are typically generated from multiple stem cells. Most interestingly they show a common clonal origin for basal, luminal and neuroendocrine cells. Similar results were also reported by Gaisa et al. [10] who also investigated PIN and malignant human prostates Again, cells deficient for a mitochondrial enzyme, cytochrome c oxidase (CCO) were identified in frozen tissue samples using dual colour enzyme histochemistry. They also demonstrate that the normal, atrophic, hypertrophic and atypical (PIN) epithelium of human prostate contains stem cell-derived clonal units that actively replenish the epithelium during ageing. These deficient areas usually included the basal compartment indicating the basal layer as the location of the stem cell. Importantly, single clonal units comprised both PIN and invasive cancer, conforming PIN as the pre-invasive lesion for prostate cancer.

 9 In situ lineage tracking of human prostatic epithelial stem cell fate reveals a common clonal origin for basal and luminal cells
Blackwood JK, Williamson SC, Greaves LC, et al.
The Journal of Pathology 2011; 225:181–188.

 10 Clonal architecture of human prostatic epithelium in benign and malignant conditions
Gaisa NT, Graham TA, McDonald SAC, et al.
The Journal of Pathology 2011; 225: 172–180.

These are really important studies and further highlight the crucial importance of in situ studies of clonal architecture and stem cell hierarchies [11,12].

 11 Stem cell identification—in vivo lineage analysis versus in vitro isolation and clonal expansion
Wright NA.
The Journal of Pathology 2012; 227:255–266.

 12 The living-tissue microscope: the importance of studying stem cells in their natural, undisturbed microenvironment
Spradling A.
The Journal of Pathology 2011; 225: 161–162.

Future therapies for metastatic carcinoma

Options for metastatic prostate cancer are limited. Androgen deprivation remains the standard of care, though most cases show escape in time and secondary therapies are only temporary. Therefore the search for new targeted therapies for hormone resistant metastatic cancer is of vital clinical importance. Akfirat et al. [13] show that survival mechanisms differ between visceral and bone metastases, suggesting therapies of the future might depend on the pattern of metastasis or a multi-drug may be appropriate in those with both visceral and bone metastases. Methods of targeting bone metastasis are investigated by Caley et al. [14] who show that the collagen receptor Endo180 participates in collagen deposition by primary human osteoblasts during de novo osteoid formation and this was suppressed by co-culture with prostate tumour cells. Immunohistochemical analysis of core biopsies from bone metastasis revealed higher levels of Endo180 expression in tumour cell foci than cells in the surrounding stroma providing a rationale for targeting collagen remodelling by Endo180 in bone metastases of prostate cancer. Recent interest has focused on the potential of targeting metabolic pathways that may be altered during prostate tumorigenesis and progression. Flavin et al. [15] have reviewed in detail metabolic changes in prostate cancer and in particular the role of fatty acid and cholesterol secretion. Over-expression of the enzyme fatty acid synthase FASN has been suggested as a diagnostic marker in prostate cancers and several small molecule inhibitors of FASN have now been described or are in development.

Overexpression of the pro-survival protein heme oxygenase-1 (HO-1) and loss of the pro-apoptotic tumour suppressor PTEN are common events in prostate cancer (PCA). Li et al. [16] assessed these proteins in men with localized and castration-resistant prostate cancer (CRPC). The combined status of both markers correlated with disease progression. In a preclinical model, inhibition of HO-1 in PTEN-deficient PC3M cell lines and their matched cells where PTEN is restored strongly reduced cell growth and lung metastasis in xenografts. The cooperation between epithelial HO-1 expression and PTEN deletions could lead to the discovery of novel therapeutic modalities. Fibroblast growth factors (FGFs) have oncogenic roles in many cancers including prostate cancer. Rococa et al. show [17] pentraxin-3 (PTX3) acts as a natural FGF antagonist and show in murine and human cultured prostate cancer cells that it has an anti-mitogenic and anti-angiogenic effects and shows decreased expression in clinical prostate cancer samples. It may be another route to target metastatic disease.

 13 Tumor Cell Survival Mechanisms in Lethal Metastatic Prostate Cancer Differ Between Bone and Soft Tissue Metastases
Akfirat C, Zhang X, Ventura A, et al.
The Journal of Pathology 2013; Accepted manuscript online. DOI: 10.1002/path.4180

 14 TGFβ1–Endo180-dependent collagen deposition is dysregulated at the tumour–stromal interface in bone metastasis
Caley MP, Kogianni G, Adamarek A, et al.
The Journal of Pathology 2012; 226:775–783, Corrected by: Corrigendum: 2013; 229: e4.

 15 Metabolic alterations and targeted therapies in prostate cancer
Flavin R, Zadra G and Loda M.
The Journal of Pathology 2011; 223:284–295.

 16

PTEN deletion and heme oxygenase-1 overexpression cooperate in prostate cancer progression and are associated with adverse clinical outcome
Li Y, Su J, DingZhang X, et al.
The Journal of Pathology 2011; 224: 90–100.

 17

Long Pentraxin-3 As An Epithelial-Stromal Fibroblast Growth Factor-Targeting Inhibitor In Prostate Cancer
Ronca R, Alessi P, Coltrini D, et al.
The Journal of Pathology 2013; Accepted manuscript online. DOI: 10.1002/path.4181

Questions

The following questions can be answered by reading and reflecting upon the above annotation and the papers that are cited within it. Within the Royal College of Pathologists Continuing Professional Development (CPD) scheme, CPD points may be earned by writing reflective notes on the papers in this Virtual Issue and the questions are designed to act as a focus for this activity. To do this, you may wish to use the Royal College of Pathologists' reflective notes form.

 Question 1 What molecular abnormalities and in particular translocations have been described in prostate cancer?

 Question 2 Outline the stem cell structure of the prostate. What are the advantages of in situ methods for analyzing clonal architecture?

 Question 3 What are the possible metabolic changes seen in prostate cancer cells?


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