Abstract
The conference took place 15 min from downtown Tokyo and talks covered a range of topics in prostate, breast and ovarian cancer. There were approximately 160 attendees from across Southeast Asia and Australia, as well as Europe and North America. Numerous high-quality posters were presented and the best abstracts were selected for short talks alongside the 20 talks from invited speakers. In this short report of the meeting, we aim to highlight some, but not all, of these talks and therefore we apologize to those that were not included in the interests of space and brevity.
The conference opened with a plenary talk by Hsing-Jien Kung (University of California Davis, CA, USA) entitled ‘Targeting tyrosine kinases and autophagy in hormone-refractory prostate cancer’. The first part of his talk focused on arginine deprivation as a strategy for inducing metabolic stress and cell death in prostate cancer Citation[1]. Arginine is a semi-essential amino acid that is synthesized from citrulline by argininosuccinate synthetase. Although argininosuccinate synthetase is expressed by normal prostatic epithelium, for reasons not entirely understood, the expression of this enzyme is lost in prostate cancer. The arginine pools within tumor cells can be further diminished by treatment of the cells with polyethylene glycol-conjugated arginine deiminase, an enzyme that hydrolyzes arginine to citrulline. Depletion of this single amino acid by arginine deiminase results in a caspase-independent autophagic cell death in prostate cancer cell lines. Inhibition of this autophagic response with chloroquine results in decreased ATP pools, which, in turn, results in an increased apoptotic response that is synergistic with that induced by taxane treatment. The second part of the presentation focused on the role of Src in mediating neuropeptide-induced androgen resistance Citation[2]. Prostate tumors commonly acquire androgen-independent growth potential. One mechanism behind this is increased neuropeptide (e.g., bombesin) secretion by the tumor cells. These neuropeptides bind to their G-protein-coupled receptors, which in turn activate Src; Src then transactivates the androgen receptor (AR) by phosphorylating it. Treatment of AI tumor cells with Src-specific inhibitors could decrease tumor cell growth in vitro and metastasis in an in vivo xenograft model.
In the second talk of the conference, Norman Maitland (University of York, UK) spoke about two related topics: the isolation and phenotyping of prostate cancer stem cells (CSCs) and possible therapies that would target this cell population. His work aims to do this using primary tissue from human patient samples since cell lines have been maintained on plastic for decades and may not reflect prostate tumors. However, since tumors are heterogeneous in cell type compared with cell lines, it can be a very difficult area for experimental study. Samples are small but his group made the discovery that stem cells from human prostate tumors can be isolated by rapid adherence to collagen through β1-integrin and selection for the cell surface antigen CD133. The grafting of isolated prostate CSCs with stroma into immune-deficient mice grows tumors with identical histology and genetic lesions to the donor sample. Gene expression profiling of the prostate CSCs has established them to be basal and AR-, even though the stem cells are isolated from AR+ luminal tumors. Other genes that are expressed in stem cells but not proliferative cells include the TMPRSS2 fusion gene, KIT and endothelial genes. Maitland concluded that targeting these pathways may be increasingly important since prostate CSCs are likely to be resistant to current androgen ablating, radio- and chemotherapies.
In the first ‘state of the art’ lecture, given on the second morning, Thea Tlsty (University of California, San Francisco, CA, USA) gave a presentation outlining her research on the genetic, epigenetic and functional alterations in early breast cancer. Ductal carcinoma in situ (DCIS) is a nonobligate precursor of breast cancer. For every ten DCIS lesions detected, only one to two will develop into invasive cancer. As a result of this, most women diagnosed with DCIS are overtreated. To date, no single parameter is able to discriminate those lesions that will not progress from those that will. By focusing on changes in premalignant tissue, Tlsty has demonstrated that overexpression of p16 (a protein normally associated with senescence) along with expression of Ki67, identifies cells that have bypassed the senescence barrier, and that this combination of markers is suitable for identifying DCIS lesions that are at risk of progressing to invasive breast cancer Citation[3]. Similar results are also observed when both Cox-2 and Ki67 are expressed by DCIS lesions. Cox2+p16+ cells are also present in apparently ‘normal’ human breast tissue; these cells are relatively rare, have eroded telomeres and are susceptible to epigenetic instability. Tlsty concluded her talk by describing how tumor microenvironment, particularly cancer-associated fibroblasts, can induce epigenetic changes that promote epithelial to mesenchymal transition and tumorigenesis.
Later in the morning, we heard from Michael Lisanti (Thomas Jefferson University, PA, USA) who gave an excellent presentation describing a new model in which autophagy in the tumor stroma fuels tumor growth and metastasis. It has long been recognized that tumor cells display the Warburg effect, that is, tumor cells have a high rate of anaerobic glycolysis when compared with normal cells. The new model describes a ‘reverse Warburg effect’ occurring in the stroma such that the stromal cells undergo autophagy, aerobic glycolysis and produce lactate and pyruvate, which in turns fuels the energy requirements of the neighboring epithelial tumor cells. Stromal cells that undergo this autophagic response have the ability to promote a field cancerization effect in which neighboring normal stromal cells also undergo this autophagic response Citation[4]. This autophagic response in the stroma can be detected by the loss of caveolin-1, which is a marker of poor prognosis in breast cancer regardless of tumor subtype Citation[5,6]. Loss of caveolin-1 can also predict response to tamoxifen, and in prostate cancer is associated with metastasis and Gleeson grade Citation[7].
In the second state of the art lecture, Yasuke Nakamura (University of Tokyo, Japan) spoke about genome-wide association studies in breast cancer. Amongst other genes, these studies have identified CYP2D6 polymorphisms as having a role in response to tamoxifen, although some studies have failed to confirm this finding. CYP2D6 encodes an enzyme important for the production of endoxifen, which is the active form of tamoxifen. A total of 20% of Japanese people are homozygous for the unfavorable allele of CYP2D6 and have a worse prognosis when treated with tamoxifen compared with the rest of the population. Further analysis of this cohort suggests that it is only those who receive monotherapy with tamoxifen who have the CYP2D6 gene association. In patients receiving combination therapies, there is no association, perhaps explaining why some studies fail to find a significant effect of CYP2D6 alleles on prognosis.
Next, Subrata Sen (MD Anderson Cancer Center, TX, USA) gave a presentation describing the role of estrogen in regulating the expression of aurora A kinase (AURKA). AURKA is a kinase involved in centrosome maturation, mitotic spindle assembly and segregation of the chromosomes during mitosis Citation[8]. This kinase is overexpressed in approximately 75% of all DCIS, but is overexpressed at lower frequencies in invasive breast tumors Citation[9]. The AURKA gene is oncogenic since overexpression leads to transformation of cells in vitroCitation[10]. Sen presented data demonstrating that expression of AURKA is higher in estrogen receptor-α+ (Erα+) than in ERα- breast cancer cells, that there is a GATA-3 binding site in the promoter of the AURKA gene and that estrogen enhances recruitment of GATA-3 to this promoter. He concluded his talk by presenting data demonstrating that AURKA itself reduces ERα transactivation activity via phosphorylation and inactivation of p53, and sequestering of ERα in the cytoplasm by p53, which in turn may promote the transition to an ERα- phenotype and tamoxifen resistance.
In the afternoon, Pradip Roy-Burman (University of Southern California, CA, USA) reported that signals originating from cancer-associated fibroblasts (CAF) may positively regulate proliferation and tumorigenicity in prostate cancer. In this study, his group investigated whether CAFs may regulate the biology of prostate CSCs by using a conditional Pten-deletion mouse model of prostate adenocarcinoma to isolate both CAF cultures and CSC-enriched cell fractions from the tumors. CSCs that were isolated possessed self-renewal, spheroid-forming and multipotential differentiation activities in tissue culture, segregating with a cell fraction exhibiting a signature expression phenotype, including Sca-1 (high), CD49f (high), cytokeratin (CK)5 (high), p63 (high), Survivin (high), Runx2 (high), CD44 (low), CD133 (low), CK18 (low) and AR (low). CSC spheroid-forming efficiency was differentially influenced by the nature of fibroblasts in a coculture system. Compared with mouse urogenital sinus mesenchyme or normal prostate fibroblasts, CAFs enhanced spheroid formation, with the spheroids displaying generally larger sizes and more complex histology. Graft experiments showed that CSCs admixed with CAFs produced prostatic glandular structures with more numerous lesions, high proliferative index, and tumor-like histopathologies, compared with those formed in the presence of normal prostate fibroblasts. He concluded that, overall, their findings reveal a significant role of CAFs in CSC biology.
In the third state of the art lecture on the final morning of the meeting, Peter Nelson (Fred Hutchinson Cancer Center, WA, USA) gave a talk outlining the role of transmembrane serine protease 2 (TMPRSS2) in prostate cancer progression. The TMPRSS2 gene is an androgen-regulated gene that is often fused with the ETS transcription factors ERG and ETV1 Citation[11]. This overexpression of TMPRSS2 results in increased expression of MET (the receptor for hepatocyte growth factor) and increased epithelial to mesenchymal transition and metastatic behavior. He also presented a model to explain the paradoxical observation that as men age, prostate cancer risk increases despite decreased circulating levels of testosterone. His data demonstrate that decreased circulating levels of testosterone result in decreased expression of claudins in the prostate, which results in increased permeability of tight junctions of the blood–prostate barrier. Loss of this barrier results in a prostate-specific inflammatory immune response, which in turn increases prostate cancer risk.
Overall, the meeting benefited from an excellent discussion on all aspects of hormonal oncogenesis. The organizers had allowed at least 15 min for discussion after each speaker and this permitted a wide-ranging discussion, reminiscent of Gordon Research Conferences. On the second day, we also took our lead from the Gordon Research Conferences and used the afternoon for an organized tour of Tokyo, visiting the Imperial Palace and Sensoji Buddhist Temple in the Asakusa district. This enabled continuing scientific and other discussions before returning for a lively poster session in the evening.
Financial & competing interests disclosure
John Stingl would like to acknowledge the support of Cancer Research UK, the University of Cambridge and Hutchinson Whampoa Limited. Robert B Clarke is funded by a Breast Cancer Campaign Fellowship. John Stingl is a consultant with StemCell Technologies Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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