Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.

/pdf/castration-resistance-in-human-prostate-cancer-is-conferred-1bwnxbltzb.pdf

Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant

The immense majority of genes are alternatively spliced and there are many isoforms specifically associated with cancer progression and metastasis. The splicing pattern of specific isoforms of numerous genes is altered as cells move through the oncogenic process of gaining proliferative capacity, acquiring angiogenic, invasive, antiapoptotic and survival properties, becoming free from growth factor dependence and growth suppression, altering their metabolism to cope with hypoxia, enabling them to acquire mechanisms of immune escape, and as they move through the epithelial-mesenchymal and mesenchymal-epithelial transitions and metastasis. Each of the 'hallmarks of cancer' is associated with a switch in splicing, towards a more aggressive invasive cancer phenotype. The choice of isoforms is regulated by several factors (signaling molecules, kinases, splicing factors) currently being identified systematically by a number of high-throughput, independent and unbiased methodologies. Splicing factors are de-regulated in cancer, and in some cases are themselves oncogenes or pseudo-oncogenes and can contribute to positive feedback loops driving cancer progression. Tumour progression may therefore be associated with a coordinated splicing control, meaning that there is the potential for a relatively small number of splice factors or their regulators to drive multiple oncogenic processes. The understanding of how splicing contributes to the various phenotypic traits acquired by tumours as they progress and metastasise, and in particular how alternative splicing is coordinated, can and is leading to the development of a new class of anticancer therapeutics-the alternative-splicing inhibitors.

Hallmarks of alternative splicing in cancer.

Nimrod, a Putative Phagocytosis Receptor with EGF Repeats in Drosophila Plasmatocytes

We use the Drosophila melanogaster larval hematopoietic system as an in vivo model for the genetic and functional genomic analysis of oncogenic cell overproliferation. Ras regulates cell proliferation and differentiation in multicellular eukaryotes. To further elucidate the role of activated Ras in cell overproliferation, we generated a collagen promoter-Gal4 strain to overexpress Ras V12 in Drosophila hemocytes. Activated Ras causes a dramatic increase in the number of circulating larval hemocytes (blood cells), which is caused by cellular overproliferation. This phenotype is mediated by the Raf/MAPK pathway. The mutant hemocytes retain the ability to phagocytose bacteria as well as to differentiate into lamellocytes. Microarray analysis of hemocytes overexpressing Ras V12 vs. Ras + identified 279 transcripts that are differentially expressed threefold or more in hemocytes expressing activated Ras. This work demonstrates that it will be feasible to combine genetic and functional genomic approaches in the Drosophila hematopoietic system to systematically identify oncogene-specific downstream targets.

https://www.genetics.org/content/genetics/163/1/203.full.pdf

Analysis of Ras-induced overproliferation in Drosophila hemocytes.

Immunotherapy, with an increasing number of therapeutic dimensions, is becoming an important mode of treatment for cancer patients. The inhibition of immune checkpoints, which are the source of immune escape for various cancers, is one such immunotherapeutic dimension. It has mainly been aimed at T cells in the past, but NK cells are a newly emerging target. Simultaneously, the number of checkpoints identified has been increasing in recent times. In addition to the classical NK cell receptors KIRs, LIRs, and NKG2A, several other immune checkpoints have also been shown to cause dysfunction of NK cells in various cancers and chronic infections. These checkpoints include the revolutionized CTLA-4, PD-1, and recently identified B7-H3, as well as LAG-3, TIGIT & CD96, TIM-3, and the most recently acknowledged checkpoint-members of the Siglecs family (Siglec-7/9), CD200 and CD47. An interesting dimension of immune checkpoints is their candidacy for dual-checkpoint inhibition, resulting in therapeutic synergism. Furthermore, the combination of immune checkpoint inhibition with other NK cell cytotoxicity restoration strategies could also strengthen its efficacy as an antitumor therapy. Here, we have undertaken a comprehensive review of the literature to date regarding NK cell-based immune checkpoints.

NK Cell-Based Immune Checkpoint Inhibition

The transforming growth factors (TGF)-β, TGF-β1, TGF-β2 and TGF-β3, and their receptors [TβRI, TβRII, TβRIII (betaglycan)] elicit pleiotropic functions in the prostate. Although expression of the ligands and receptors have been investigated, the splice variants have never been analyzed. We therefore have analyzed all ligands, the receptors and the splice variants TβRIB, TβRIIB and TGF-β2B in human prostatic cells. Interestingly, a novel human receptor transcript TβRIIC was identified, encoding additional 36 amino acids in the extracellular domain, that is expressed in the prostatic cancer cells PC-3, stromal hPCPs, and other human tissues. Furthermore, the receptor variant TβRIB with four additional amino acids was identified also in human. Expression of the variant TβRIIB was found in all prostate cell lines studied with a preferential localization in epithelial cells in some human prostatic glands. Similarly, we observed localization of TβRIIC and TGF-β2B mainly in the epithelial cells with a preferential localization of TGF-β2B in the apical cell compartment. Whereas in the androgen-independent hPCPs and PC-3 cells all TGF-β ligands and receptors are expressed, the androgen-dependent LNCaP cells failed to express all ligands. Additionally, stimulation of PC-3 cells with TGF-β2 resulted in a significant and strong increase in secretion of plasminogen activator inhibitor-1 (PAI-1) with a major participation of TβRII. In general, expression of the splice variants was more heterogeneous in contrast to the well-known isoforms. The identification of the splice variants TβRIB and the novel isoform TβRIIC in man clearly contributes to the growing complexity of the TGF-β family.

/pdf/alternative-splicing-of-tgf-betas-and-their-high-affinity-5eafk783mw.pdf

Alternative splicing of TGF-betas and their high-affinity receptors TβRI, TβRII and TβRIII (betaglycan) reveal new variants in human prostatic cells

Cloning, structure, cellular localization, and possible function of the tumor suppressor gene lethal(3)malignant blood neoplasm-1 of Drosophila melanogaster.

BACKGROUND We examined the expression of CD200, a ligand of immune tolerance, in transitional cell carcinoma of the human bladder (TCC). MATERIALS AND METHODS CD200 was analyzed by immunohistochemistry (IHC) in 90 patients with suspected TCC lesions of the bladder. Expression of CD200 was exemplarily validated by quantitative reverse transcription polymerase chain reaction and western blot analysis. RESULTS CD200 was detectable at mRNA and protein levels in TCC homogenate and TCC cell lines (T24, UMUC3). TCC tissues showed significantly higher CD200 expression (p<0.005) than normal bladder tissues. CD200 signals were also higher in metastasized compared to localized TCC (p<0.05). CD200 was significantly correlated to tumor grading (p<0.001) and was strongest in the subgroup with high-grade G2 TCC (vs. low-grade G2 p<0.05). CONCLUSION This is the first report of CD200 expression in patients with TCC. The significant correlation between CD200 expression and tumor grading may suggest CD200 as a potential target and marker for immunotherapeutic approaches.

/pdf/the-immune-checkpoint-molecule-cd200-is-associated-with-4nnp0i3jve.pdf

The Immune Checkpoint Molecule CD200 Is Associated with Tumor Grading and Metastasis in Bladder Cancer.

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Alternative splicing of TGF-betas and their high-affinity receptors TβRI, TβRII and TβRIII (betaglycan) reveal new variants in human prostatic cells

Cloning, structure, cellular localization, and possible function of the tumor suppressor gene lethal(3)malignant blood neoplasm-1 of Drosophila melanogaster.

The Immune Checkpoint Molecule CD200 Is Associated with Tumor Grading and Metastasis in Bladder Cancer.