Does EIF2S3 Retrogene Activation Regulate Cancer/Testis Antigen Expression in Human Cancers?

Cancer/Testis (C/T) antigens are a group of antigens, expressed in almost all types of cancers, which can elicit an immune response in patients whose cancers express these antigens. They are currently of great interest as targets for the development of cancer biomarkers and the creation of immunotherapies that directly target tumors in patients. Currently there are 280 C/T antigens and their variants listed on the C/T antigen data base. All known C/T antigens are encoded for by genes which are normally only expressed in the male testis; specifically during the process of spermatogenesis. They are therefore only expressed in germ cells that are in the process of differentiating into sperm. Expression of C/T antigens in tumors is thus a biological anomaly as, with the exception of germ cell tumors, cancers arise from somatic tissues which are not known to express any of the genes specifically involved in spermatogenesis. How and why C/T antigens are expressed in tumors remains an enigma. In this paper we present a hypothesis which proposes a mechanism for the activation of C/T antigen encoding genes in tumors. We propose that aberrant activation of the human autosomal retrogene, EIF2S3B, which regulates initiation and maintenance of spermatogenesis in males, is responsible for C/T expression. Because both male and females have tumors that express C/T antigens activation of spermatogenesis genes in tumors must involve a non-sex specific pathway. This can be explained by the copy number of EIF2S3 genes uniquely present within the human genome.

Successful yolk-sac tumor treatment with fertility-sparing partial oophorectomy.

Yolk-sac tumors account for about 20% of ovarian germ cell tumors and occur predominantly in women below 35 years of age. Modern evidence-based treatment strategies have ensured long term post-treatment survival, but with increased survival, attention has been turned to an urgent need for developing fertility sparing treatment strategies. In this report we describe the successful treatment of a young woman who was able to conceive and deliver two children, in spite of the loss of one ovary two years prior to being diagnosed with an ovarian yolk-sac tumor on the remaining ovary.

Do some epithelial ovarian cancers originate from a fallopian tube ciliate cell lineage?

There is a general agreement that a large subpopulation of serous ovarian cancers arise from the fallopian tube mucosal epithelium. However, there is still some debate as to whether the cancers originate from a secretory or ciliate cell lineage. One well established method for determining the origin of a cell line is to document the expression of genes and proteins that are cell type specific. Lineage or tissue specific patterns of gene expression are evidence of direct decent from a given cell type within a tissue. It has recently been established that the Tumor Protein TAp73 gene (TP73) is expressed in basal epithelial cells that develop into multiciliate cells. TP73 expression is therefore a marker for basal stem cells that are predestined to differentiate into cells with motile cilia and its expression is maintained in fully differentiated multiciliate cells. Interestingly TP73 expression has also been observed in a high percentage of epithelial ovarian cancers. With this in mind, it is hypothesized that a high percentage of epithelial ovarian cancers which express TP73 originate from a ciliate cell lineage.

Piwil2-transfected human fibroblasts are cancer stem cell-like and genetically unstable.

Uncontrolled cell proliferation and inhibition of apoptosis are considered to be vital for cancer initiation, maintenance, infiltration, metastasis and recurrence after anti-cancer therapy. Here we report the generation of a novel cell line by reprogramming child foreskin fibroblast with the full length apoptosis inhibitor gene PIWIL2. The fibroblasts transfected with PIWIL2 expressed the stem cell markers OCT-4, NANOG, SOX-2, KLF-4 and C-MYC; endoderm marker AFP and GATA6; mesoderm markers ACTA2 and BRACHYURY; and ectoderm markers NESTIN and TUBB3. The karyotype was found to be hyperdiploid. The PIWIL2 transfected fibroblast cells grew into tumorous masses within 5 weeks of subcutaneous injection into adult nude mice. Although the injected cell expressed markers for all three germlines, ectoderm, mesoderm, and endoderm, they did not form teratomas in vivo. This study indicates that the PIWIL2 gene could play a key role in cancer induction and maintenance. This method for generating induced tumorigenic cells (ITGC) provides a new research tool to study oncogenesis that in turn may lead to a better understanding of cancer etiology and the development of novel anti-cancer therapies.

Multipotential differentiation of human urine-derived stem cells: potential for therapeutic applications in urology.

We sought to biologically characterize and identify a subpopulation of urine-derived stem cells (USCs) with the capacity for multipotent differentiation. We demonstrated that single USCs can expand to a large population with 60-70 population doublings. Nine of 15 individual USC clones expressed detectable levels of telomerase and have long telomeres. These cells expressed pericyte and mesenchymal stem cell markers. Upon induction with appropriate media in vitro, USCs differentiated into bladder-associated cell types, including functional urothelial and smooth muscle cell lineages. When the differentiated USCs were seeded onto a scaffold and subcutaneously implanted into nude mice, multilayered tissue-like structures formed consisting of urothelium and smooth muscle. Additionally, USCs were able to differentiate into endothelial, osteogenic, chondrogenic, adipogenic, skeletal myogenic, and neurogenic lineages but did not form teratomas during the 1-month study despite telomerase activity. USCs may be useful in cell-based therapies and tissue engineering applications, including urogenital reconstruction.

Does expression of the retrogene UTP14c in the ovary pre-dispose women to ovarian cancer?

It has been previously shown that the spermatogenesis associated retrogene, UTP14c, is expressed in over 50% of normal human ovaries and 80% of ovarian cancers. UTP14c is located on chromosome 13 as an intronless copy of the X-linked housekeeping gene, UTP14a. Like all spermatogenesis associated retrogenes, UTP14c is expressed in the testis and is essential for sperm production. It has no known role in the female and is not normally expressed in any cells or organs outside of the gonads. By comparison the protein encoded by UTP14a is found in all cell types and has a dual function. It is primarily involved in the biosynthesis of 18S ribosomal RNA in the nucleolus where it is a component of the U3 small nucleolar RNA associated protein complex. In addition, it down regulates TP53 in both the nucleus and cytoplasm by targeting it for proteolytic degradation. By analogy, we propose that the UTP14c peptide also targets TP53 for degradation. This in turn may prevent cells expressing UTP14c from entering apoptosis. The loss of TP53 in ovarian cells can also result in the down regulation of microRNA-145 (miR-145) expression. The loss of miR-145 can result in the activation of factors that promote oncogenesis and cellular pluripotency which in turn could lead to the development of ovarian cancer. We hypothesize that women, whose ovaries express UTP14c, are predisposed to ovarian cancer due to the disruption of protective signals that normally trigger TP53-mediated apoptosis and the dysregulation of genes that promote oncogenesis, such as c-Myc, that occurs when miR-145 synthesis is disrupted.

Spermatogenesis associated retrogenes are expressed in the human ovary and ovarian cancers.

BACKGROUND: Ovarian cancer is the second most prevalent gynecologic cancer in women. However, it is by far the most lethal. This is generally attributed to the absence of easily detectable markers specific to ovarian cancers that can be used for early diagnosis and specific therapeutic targets. METHODOLOGY/PRINCIPAL FINDINGS: Using end point PCR we have found that a family of retrogenes, previously thought to be expressed only in the male testis during spermatogenesis in man, are also expressed in normal ovarian tissue and a large percentage of ovarian cancers. In man there are at least eleven such autosomal retrogenes, which are intronless copies of genes on the X chromosome, essential for normal spermatogenesis and expressed specifically in the human testis. We tested for the expression of five of the known retrogenes, UTP14C, PGK2, RPL10L, RPL39L and UBL4B in normal human ovary and ovarian cancers. CONCLUSIONS/SIGNIFICANCE: We propose that the activation of the testis specific retrogenes in the ovary and ovarian cancers is of biological significance in humans. Because these retrogenes are specifically expressed in the ovary and ovarian cancers in the female they may prove useful in developing new diagnostic and/or therapeutic targets for ovarian cancer.