
| Written | 2013-11 | Swetha Yadav, Robert J Amato, Virginia Mohlere |
| Department of Internal Medicine/Division of Oncology, The University of Texas Health Science Center at Houston, Houston, TX, USA |
| Identity |
| Alias_symbol (synonym) | 5T4-AG |
| 5T4 | |
| Other alias | 5T4AG |
| M6P1 | |
| HGNC (Hugo) | TPBG |
| LocusID (NCBI) | 7162 |
| Atlas_Id | 42675 |
| Location | 6q14.1 [Link to chromosome band 6q14] |
| Location_base_pair | Starts at 82364244 and ends at 82367416 bp from pter ( according to hg19-Feb_2009) [Mapping TPBG.png] |
| Local_order | Size: 7623 bp; orientation: plus strand. |
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| Figure 1. Adapted from Ensembl. | |
| DNA/RNA |
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| Figure 2. Adapted from NCBI. | |
| Description | The gene has 8 distinct introns. |
| Transcription | Transcription results in the production of 9 different mRNA, 8 alternatively spliced forms and 1 unspliced form. The mRNA differ by truncation of the 5 prime end, presence or absence of 2 cassette exons, overlapping exons with different boundaries, splicing versus retention of 3 introns. The mRNA aAug10 variant has 2590 bp and the premessenger has a single exon. bAug10 has 3395 bp and the premessenger has 3 exons, cAug10 has 3446 bp and the premessenger has 2 exons, dAug10 has 817 bp and the premessenger has 3 exons, eAug10 has 687 bp and the premessenger has 3 exons, fAug10 has 607 bp and the premessenger has 3 exons, gAug10 has 591 bp and the premessenger has 2 exons, hAug10 has 564 bp and the premessenger has 2 exons, iAug10 has 568 bp and the premessenger has 2 exons. The gene has 3 transcripts or 3 splice variants as per Ensembl. These 3 variants are subsets of the 8 spliced variants as per GenBAnk, bdEST, Trace and SRA databases supervised by the AceView program. |
| Protein |
| Note | There is evidence at the protein level. |
| Description | This is a 420-amino acid protein that contains an N-terminal putative signal sequence, a 310-residue extracellular region, a membrane anchorage domain, and a 44-amino acid cytoplasmic tail with a potential phosphorylation site. The extracellular region has 7 potential N-glycosylation sites and 7 leucine-rich repeats, which are located in 2 regions separated by a hydrophilic stretch (Myers et al., 1994). Genomic sequence analysis reveals that the gene has 2 exons, the second of which encodes the protein (King et al., 1999). Sequence Isoforms |
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| Table 1. Reactivity of monoclonal antibody 5T4 with normal human tissues. Immunohistological analysis of frozen sections. Adapted from Hole and Stern, Br. J. Cancer (1988). | |
| Expression | TPBG is expressed by all types of trophoblasts by as early as 9 weeks of development. The gene is specific for trophoblastic cells except for amniotic epithelium. This has been demonstrated by immunoperoxidase staining of frozen sections. Expression is limited to few epithelial subtypes in adult tissue but is found to be widely expressed on a number of different carcinomas (Southall et al., 1990). It has a molecular weight of 72 kD. It is a glycoprotein with a 42-kDa core protein with extensive N-linked glycosylation. It exists on the cell surface as a monomeric protein. The mature protein is membrane bound and consists of 310 amino acid extracellular regions with 7 N-linked glycosylation sites and a short 44-amino acid cytoplasmic tails. There are 7 leucine rich repeats in the extracellular portion. The LRRs are believed to mediate protein-protein interactions (Carsberg et al., 1995). |
| Localisation | Membrane, single-pass type I membrane protein. |
| Function | - Cell adhesion Transduction into cell lines enhances cell motility and decreases cell-to-cell contact, thereby playing a role in tumor invasion and metastases. This has been demonstarated in mouse fibroblasts (Carsberg et al., 1996). - Chemotaxis It has also been demonstrated that CXCR4-mediated chemotaxis is regulated by 5T4 as shown in mouse embryonic cells. CXCR4 mediates the migration of cells to tissues rich in CXCL12 (Southgate et al., 2010). - EMT The 5T4 antigen has been shown to play an important role in the epithelial-to-mesenchymal transition. The EMT is a process that occurs in early embryonic cells as well as metastases of certain cancers. The main events that occur during this process are a switch from E cadherin to N cadherin, increased vimentin expression, up-regulation of E cadherin repressor molecules such as snail and slug proteins, increased matrix metalloproteinases such as MMP2 and MMP9, and cellular motility. The role of 5T4 in the process of EMT has been demonstrated in experiments on embryonic stem cells (Ensembl). - Pathways and interaction There is 1 interacting protein for TPBG-GIPC1 (MINT). Full expression of 5T4 is found to transform mouse mammary epithelial cells to dendritic morphology. This is accompanied by loss of actin/adherin junctions, down regulation of ecadherin and changes in the cytoskeleton. These changes do not occur in the absence of the cytoplasmic tail portion of 5T4. G1PC is a scaffolding protein that interacts with the cytoplasmic tail of 5T4 and it contains the PDZ protein (Lee et al., 2008). PDZ domains mediate protein-protein interactions.The interaction between GIPC1 and 5T4 was demonstrated in HeLa cells using the yeast two hybrid approach by Awan et al. (2002). This interaction indicates a role for 5T4 in mediating changes within the cytoskeleton and thereby it's role in invasion and metastases. |
| Homology | Orthologs are present from 14 different species with the homology varying from 22% to 99% The greatest homology was with Pan troglotydes species (chimpanzee) with 99,68% homology based on the nucleic acids and 99,52% homology based on amino acids comparison to the human gene (Ensembl). There is 1 paralogue (Ensembl). |
| Mutations |
| Note | Summary of gene variation consequences (Ensembl) There are a total of 921 variant sequences and 33 structural variations as summarized by the Ensembl data base. This includes 6 frameshift mutations, 6 stop gained mutations, 3 inframe deletions, 153 misense variants, 2 splice region variants,111 synonymous variants,26 - 5 prime UTR variants,117- 3 prime UTR variants,22 intron variants, 179 upstream gene variants and 298 downstream gene variants. Structural variations: there are 12 copy number variations, 2 insertions, 2 inversions, 4 tandem duplications and 13 intrachromosomal breakpoints. |
| Implicated in |
| Note | |
| Entity | Gastric carcinoma |
| Note | 5T4 antigen is expressed in up to 81% of gastric cancers. Starzynska et al. (1992) reported that the expression of 5T4 antigen in gastric cancer correlated with the presence of nodal involvement and distant metastases. Review of pathology showed a greater association of the 5T4 antigen with the diffuse variant of gastric cancer as opposed to the intestinal type or mixed pathology. |
| Entity | Colorectal carcinoma |
| Note | 5T4 antigen is expressed in up to 85% of colorectal cancers. Its presence is associated with poor prognosis. The antigen is found more commonly in tumors that present with nodal involvement or distant metastases. This has been demonstrated by IHC staining for the 5T4 antigen. According to a paper published by Mulder et al. (1997), the 5-year survival for tumors that were 5T4 positive was 22%, compared to 75% for tumors that were 5T4 negative. Median survival was 24 months for 5T4-positive tumors, compared to >90 months for 5T4 negative tumors. This indicates that 5T4 antigen expression can be used as an indicator of aggressive disease with earlier recurrence and suggests potential benefit from adjuvant chemotherapy as opposed to 5T4-negative tumors. Drugs and compounds: TroVax |
| Entity | Renal cell carcinoma |
| Note | Griffiths et al. (2005) demonstrated the expression of 5T4 antigen in high levels in 20 cases of RCC. The sample was too small to make any conclusions regarding prognosis. The expression of 5T4 is on the membrane, making it a good candidate for targeted therapy in RCC. Phase 1 and 2 studies have demonstrated the safety and effectiveness of the TroVax vaccine in RCC. The TroVax vaccine is MVA-5T4, which is a modified virus carrying the 5T4 antigen and capable of eliciting an anti-5T4 antibody response. Drugs and compounds: TroVax |
| Entity | Cervical carcinoma |
| Note | It has been demonstrated that there is a relationship between the expression of 5T4 antigen and dysplastic conditions such as cervical intraepithelial neoplasia (CIN). Jones et al. (1990) showed a higher level of 5T4 expression in CIN grade 2 and 3 as well as invasive cervical cancer. It has been postulated that the expression of 5T4 may be directly related to the presence of the human papillomavirus. Jones et al. (1990) studied a total of 66 samples and demonstrated 100% expression of 5T4 in invasive cervical carcinoma. This indicates that 5T4 can be used as a potential tumor marker in cervical cancer. |
| Entity | Non-small cell lung carcinoma |
| Note | Damelin et al. (2011) demonstrated that 5T4 is expressed in tumor-initiating cells and is associated with a poor prognosis in NSCLC. Expression of 5T4 correlated with more undifferentiated histology, shorter time to recurrence, and worse overall survival. The expression of 5T4 correlated with markers of EMT. There were a total of 320 tumor samples in this study, 249 of which were positive for the expression of 5T4 antigen. |
| Entity | Ovarian cancer |
| Note | Wrigley et al. (1995) demonstrated that 71% of epithelial ovarian carcinomas expressed the 5T4 antigen (total sample of 72 tumors). There was a significant correlation between the expression of 5T4 antigen and advanced stage (i.e., FIGO stage 3 and 4) and an association with poorly differentiated tumors. Patients whose tumors expressed 5T4 had a worse overall survival, had shorter disease-free survival, and were less likely to respond to adjuvant therapy. |
| Entity | Prostate cancer |
| Note | Drugs and compounds: TroVax Two phase 2 trials have studied TroVax in castration-resistant prostate cancer patients. An open-label phase 2 trial by evaluated TroVax alone or in combination with GM-CSF in 27 patients with castration-resistant prostate cancer. All 24 immunologically evaluable patients mounted a 5T4 antibody response. Time to progression was significantly greater in those who mounted a 5T4-specific cellular response (5.6 vs. 2.3 months) (Amato et al., 2008a). A second phase 2 randomized study enrolled 25 patients, 12 of whom were randomzied to receive TroVax plus docetaxel and 13 to receive docetaxel alone. Patients treated with TroVax plus docetaxel had a longer PFS (9.67 months) than those in the docetaxel-alone arm (5.10 months). Six of the 10 immunologically evaluable patients mounted a 5T4 antibody response (Harrop et al., 2013). |
| Entity | Other diseases |
| Note | Association with other diseases based on cell line studies: GEO Profiles. |
| Bibliography |
| Vaccination of prostate cancer patients with modified vaccinia ankara delivering the tumor antigen 5T4 (TroVax): a phase 2 trial. |
| Amato RJ, Drury N, Naylor S, Jac J, Saxena S, Cao A, Hernandez-McClain J, Harrop R. |
| J Immunother. 2008a Jul-Aug;31(6):577-85. doi: 10.1097/CJI.0b013e31817deafd. |
| PMID 18528296 |
| Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebo-controlled phase III study. |
| Amato RJ, Hawkins RE, Kaufman HL, Thompson JA, Tomczak P, Szczylik C, McDonald M, Eastty S, Shingler WH, de Belin J, Goonewardena M, Naylor S, Harrop R. |
| Clin Cancer Res. 2010 Nov 15;16(22):5539-47. doi: 10.1158/1078-0432.CCR-10-2082. Epub 2010 Sep 29. |
| PMID 20881001 |
| Vaccination of renal cell cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) alone or administered in combination with interferon-alpha (IFN-alpha): a phase 2 trial. |
| Amato RJ, Shingler W, Goonewardena M, de Belin J, Naylor S, Jac J, Willis J, Saxena S, Hernandez-McClain J, Harrop R. |
| J Immunother. 2009 Sep;32(7):765-72. doi: 10.1097/CJI.0b013e3181ace876. |
| PMID 19561532 |
| 5T4 interacts with TIP-2/GIPC, a PDZ protein, with implications for metastasis. |
| Awan A, Lucic MR, Shaw DM, Sheppard F, Westwater C, Lyons SA, Stern PL. |
| Biochem Biophys Res Commun. 2002 Jan 25;290(3):1030-6. |
| PMID 11798178 |
| Metastasis-associated 5T4 antigen disrupts cell-cell contacts and induces cellular motility in epithelial cells. |
| Carsberg CJ, Myers KA, Stern PL. |
| Int J Cancer. 1996 Sep 27;68(1):84-92. |
| PMID 8895545 |
| CDC25B mediates rapamycin-induced oncogenic responses in cancer cells. |
| Chen RQ, Yang QK, Lu BW, Yi W, Cantin G, Chen YL, Fearns C, Yates JR 3rd, Lee JD. |
| Cancer Res. 2009 Mar 15;69(6):2663-8. doi: 10.1158/0008-5472.CAN-08-3222. Epub 2009 Mar 10. |
| PMID 19276368 |
| Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells. |
| Damelin M, Geles KG, Follettie MT, Yuan P, Baxter M, Golas J, DiJoseph JF, Karnoub M, Huang S, Diesl V, Behrens C, Choe SE, Rios C, Gruzas J, Sridharan L, Dougher M, Kunz A, Hamann PR, Evans D, Armellino D, Khandke K, Marquette K, Tchistiakova L, Boghaert ER, Abraham RT, Wistuba II, Zhou BB. |
| Cancer Res. 2011 Jun 15;71(12):4236-46. doi: 10.1158/0008-5472.CAN-10-3919. Epub 2011 May 3. |
| PMID 21540235 |
| Epithelial-mesenchymal transition events during human embryonic stem cell differentiation. |
| Eastham AM, Spencer H, Soncin F, Ritson S, Merry CL, Stern PL, Ward CM. |
| Cancer Res. 2007 Dec 1;67(23):11254-62. |
| PMID 18056451 |
| An MVA-based vaccine targeting the oncofetal antigen 5T4 in patients undergoing surgical resection of colorectal cancer liver metastases. |
| Elkord E, Dangoor A, Drury NL, Harrop R, Burt DJ, Drijfhout JW, Hamer C, Andrews D, Naylor S, Sherlock D, Hawkins RE, Stern PL. |
| J Immunother. 2008 Nov-Dec;31(9):820-9. doi: 10.1097/CJI.0b013e3181876ab3. |
| PMID 18833005 |
| Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy. |
| Griffiths RW, Gilham DE, Dangoor A, Ramani V, Clarke NW, Stern PL, Hawkins RE. |
| Br J Cancer. 2005 Sep 19;93(6):670-7. |
| PMID 16222313 |
| Vaccination of castration-resistant prostate cancer patients with TroVax (MVA-5T4) in combination with docetaxel: a randomized phase II trial. |
| Harrop R, Chu F, Gabrail N, Srinivas S, Blount D, Ferrari A. |
| Cancer Immunol Immunother. 2013 Sep;62(9):1511-20. doi: 10.1007/s00262-013-1457-z. Epub 2013 Jul 23. |
| PMID 23877659 |
| Vaccination of colorectal cancer patients with TroVax given alongside chemotherapy (5-fluorouracil, leukovorin and irinotecan) is safe and induces potent immune responses. |
| Harrop R, Drury N, Shingler W, Chikoti P, Redchenko I, Carroll MW, Kingsman SM, Naylor S, Griffiths R, Steven N, Hawkins RE. |
| Cancer Immunol Immunother. 2008 Jul;57(7):977-86. |
| PMID 18060404 |
| Vaccination of patients with metastatic renal cancer with modified vaccinia Ankara encoding the tumor antigen 5T4 (TroVax) given alongside interferon-alpha. |
| Hawkins RE, Macdermott C, Shablak A, Hamer C, Thistlethwaite F, Drury NL, Chikoti P, Shingler W, Naylor S, Harrop R. |
| J Immunother. 2009 May;32(4):424-9. doi: 10.1097/CJI.0b013e31819d297e. |
| PMID 19342962 |
| A 72 kD trophoblast glycoprotein defined by a monoclonal antibody. |
| Hole N, Stern PL. |
| Br J Cancer. 1988 Mar;57(3):239-46. |
| PMID 3355761 |
| Investigation of expression of 5T4 antigen in cervical cancer. |
| Jones H, Roberts G, Hole N, McDicken IW, Stern P. |
| Br J Cancer. 1990 Jan;61(1):96-100. |
| PMID 2404512 |
| Organisation of the mouse and human 5T4 oncofoetal leucine-rich glycoprotein genes and expression in foetal and adult murine tissues. |
| King KW, Sheppard FC, Westwater C, Stern PL, Myers KA. |
| Biochim Biophys Acta. 1999 Jun 9;1445(3):257-70. |
| PMID 10366710 |
| Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC. |
| Lee NY, Ray B, How T, Blobe GC. |
| J Biol Chem. 2008 Nov 21;283(47):32527-33. doi: 10.1074/jbc.M803059200. Epub 2008 Sep 5. |
| PMID 18775991 |
| Low intercellular adhesion molecule 1 and high 5T4 expression on tumor cells correlate with reduced disease-free survival in colorectal carcinoma patients. |
| Mulder WM, Stern PL, Stukart MJ, de Windt E, Butzelaar RM, Meijer S, Ader HJ, Claessen AM, Vermorken JB, Meijer CJ, Wagstaff J, Scheper RJ, Bloemena E. |
| Clin Cancer Res. 1997 Nov;3(11):1923-30. |
| PMID 9815581 |
| Attenuated recombinant vaccinia virus expressing oncofetal antigen (tumor-associated antigen) 5T4 induces active therapy of established tumors. |
| Mulryan K1, Ryan MG, Myers KA, Shaw D, Wang W, Kingsman SM, Stern PL, Carroll MW. |
| Mol Cancer Ther. 2002 Oct;1(12):1129-37. |
| PMID 12481437 |
| Isolation of a cDNA encoding 5T4 oncofetal trophoblast glycoprotein. An antigen associated with metastasis contains leucine-rich repeats. |
| Myers KA, Rahi-Saund V, Davison MD, Young JA, Cheater AJ, Stern PL. |
| J Biol Chem. 1994 Mar 25;269(12):9319-24. |
| PMID 8132670 |
| Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. |
| Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M. |
| Sci Signal. 2010 Jan 12;3(104):ra3. doi: 10.1126/scisignal.2000475. |
| PMID 20068231 |
| Immunohistological distribution of 5T4 antigen in normal and malignant tissues. |
| Southall PJ, Boxer GM, Bagshawe KD, Hole N, Bromley M, Stern PL. |
| Br J Cancer. 1990 Jan;61(1):89-95. |
| PMID 2404511 |
| CXCR4 mediated chemotaxis is regulated by 5T4 oncofetal glycoprotein in mouse embryonic cells. |
| Southgate TD, McGinn OJ, Castro FV, Rutkowski AJ, Al-Muftah M, Marinov G, Smethurst GJ, Shaw D, Ward CM, Miller CJ, Stern PL. |
| PLoS One. 2010 Apr 1;5(4):e9982. doi: 10.1371/journal.pone.0009982. |
| PMID 20376365 |
| The expression of 5T4 antigen in colorectal and gastric carcinoma. |
| Starzynska T, Rahi V, Stern PL. |
| Br J Cancer. 1992 Nov;66(5):867-9. |
| PMID 1419629 |
| 5T4 oncofetal antigen expression in ovarian carcinoma. |
| Wrigley E, McGown AT, Rennison J, Swindell R, Crowther D, Starzynska T, Stern PL. |
| Int J Gynecol Cancer. 1995 Jul;5(4):269-274. |
| PMID 11578488 |
| Citation |
| This paper should be referenced as such : |
| Yadav, S ; Amato, RJ ; Mohlere, V |
| TPBG (trophoblast glycoprotein) |
| Atlas Genet Cytogenet Oncol Haematol. 2014;18(7):491-496. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/TPBGID42675ch6q14.html |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Fri Jun 30 11:20:25 CEST 2017 |
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