Understanding and exploiting 5T4 oncofoetal glycoprotein expression

Stern, Peter L.; Brazzatti, Julie; Sawan, Saladin; McGinn, Owen J

doi:10.1016/j.semcancer.2014.07.004

Cited by 27 publications

(28 citation statements)

References 72 publications

(88 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5T4 is associated with differentiating embryonic stem cells, 12,13 and mechanistically associated with the directional movement of cells through the regulation of epithelial mesenchymal transition, 12–14 facilitation of CXCL12/CXCR4 chemotaxis 15,16 and favoring non-canonical over canonical WNT/β–catenin pathway signaling. 17,18 5T4 is expressed by tumor-initiating cells in human non-small cell carcinomas 19 and by a number of carcinomas. 20 The selective pattern of 5T4 tumor expression, its association with a tumor-initiating phenotype plus a mechanistic involvement with cancer spread has stimulated the development of 5T4 vaccine, 5T4 antibody targeted– superantigen and 5T4 antibody-drug conjugate (ADC) therapies through preclinical and into clinical studies.…”

Section: Introductionmentioning

confidence: 99%

Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia

et al. 2017

Self Cite

View full text Add to dashboard Cite

Outcome in childhood acute lymphoblastic leukemia is prognosticated from levels of minimal residual disease after remission induction therapy. Higher levels of minimal residual disease are associated with inferior results even with intensification of therapy, thus suggesting that identification and targeting of minimal residual disease cells could be a therapeutic strategy. Here we identify high expression of 5T4 in subclonal populations of patient-derived xenografts from patients with high, post-induction levels of minimal residual disease. 5T4-positive cells showed preferential ability to overcome the NOD-scidIL2Rγnull mouse xenograft barrier, migrated in vitro on a CXCL12 gradient, preferentially localized to bone marrow in vivo and displayed the ability to reconstitute the original clonal composition on limited dilution engraftment. Treatment with A1mcMMAF (a 5T4-antibody drug conjugate) significantly improved survival without overt toxicity in mice engrafted with a 5T4-positive acute lymphoblastic leukemia cell line. Mice engrafted with 5T4-positive patient-derived xenograft cells were treated with combination chemotherapy or dexamethasone alone and then given A1mcMMAF in the minimal residual disease setting. Combination chemotherapy was toxic to NOD-scidIL2Rγnull mice. While dexamethasone or A1mcMMAF alone improved outcomes, the sequential administration of dexamethasone and A1mcMMAF significantly improved survival (P=0.0006) over either monotherapy. These data show that specifically targeting minimal residual disease cells improved outcomes and support further investigation of A1mcMMAF in patients with high-risk B-cell precursor acute lymphoblastic leukemia identified by 5T4 expression at diagnosis.

show abstract

Section: Introductionmentioning

confidence: 99%

Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the placenta, TPBG is coexpressed with CITED2 by trophoblast cells and plays key roles in cell adhesion, migration, and proper capillary patterning. 34,35 Moreover, it has been demonstrated that hypoxia induces CITED2 gene expression through HIF (hypoxia-inducible factor)1α-mediated transcriptional induction, followed by rapid and transient upregulation of CITED2 protein. [36][37][38] In turn, CITED2 overexpression induces elevated TPBG transcripts, 39 and upregulates various components of the EMT-associated program, of which TPBG is an acknowledged member.…”

Section: Discussionmentioning

confidence: 99%

Role of TPBG (Trophoblast Glycoprotein) Antigen in Human Pericyte Migratory and Angiogenic Activity

Spencer

Jover

Cathery

et al. 2019

ATVB

View full text Add to dashboard Cite

Objective-To determine the role of the oncofetal protein TPBG (trophoblast glycoprotein) in normal vascular function and reparative vascularization. Approach and Results-Immunohistochemistry of human veins was used to show TPBG expression in vascular smooth muscle cells and adventitial pericyte-like cells (APCs). ELISA, Western blot, immunocytochemistry, and proximity ligation assays evidenced a hypoxia-dependent upregulation of TPBG in APCs not found in vascular smooth muscle cells or endothelial cells. This involves the transcriptional modulator CITED2 (Atypical chemokine receptor 3 CBP/ p300-interacting transactivator with glutamic acid (E)/aspartic acid (D)-rich tail) and downstream activation of CXCL12 (chemokine [C-X-C motif] ligand-12) signaling through the CXCR7 (C-X-C chemokine receptor type 7) receptor and ERK1/2 (extracellular signal-regulated kinases 1/2). TPBG silencing by siRNA transfection downregulated CXCL12, CXCR7, and pERK (phospho Thr202/Tyr204 ERK1/2) and reduced the APC migratory and proangiogenic capacities. TPBG forced expression induced opposite effects, which were associated with the formation of CXCR7/CXCR4 (C-X-C chemokine receptor type 4) heterodimers and could be contrasted by CXCL12 and CXCR7 neutralization. In vivo Matrigel plug assays using APCs with or without TPBG silencing evidenced TPBG is essential for angiogenesis. Finally, in immunosuppressed mice with limb ischemia, intramuscular injection of TPBG-overexpressing APCs surpassed naïve APCs in enhancing perfusion recovery and reducing the rate of toe necrosis. Conclusions-TPBG orchestrates the migratory and angiogenic activities of pericytes through the activation of the CXCL12/ CXCR7/pERK axis. This novel mechanism could be a relevant target for therapeutic improvement of reparative angiogenesis. Visual Overview-An online visual overview is available for this article.

show abstract

“…WAIF1 is a vertebrate‐specific single‐spanning transmembrane glycoprotein first identified in human placenta . Because WAIF1 was also detected in several cancers, it was considered as a candidate molecular target in cancer . Although chemokine receptor CXCR4‐mediated chemotaxis is regulated by WAIF1 in mouse embryonic cells, the mechanism underlying WAIF1 interaction with CXCR4 is unclear.…”

Section: Discussionmentioning

confidence: 99%

WAIF1 Is a Cell-Surface CTHRC1 Binding Protein Coupling Bone Resorption and Formation

Matsuoka

Kohara

Naoe

et al. 2018

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

The osteoclast-derived collagen triple helix repeat containing 1 (CTHRC1) protein stimulates osteoblast differentiation, but the underlying mechanism remains unclear. Here, we identified Wnt-activated inhibitory factor 1 (WAIF1)/5T4 as a cell-surface protein binding CTHRC1. The WAIF1-encoding Trophoblast glycoprotein (Tpbg) gene, which is abundantly expressed in the brain and bone but not in other tissues, showed the same expression pattern as Cthrc1. Tpbg downregulation in marrow stromal cells reduced CTHRC1 binding and CTHRC1-stimulated alkaline phosphatase activity through PKCδ activation of MEK/ERK, suggesting a novel WAIF1/PKCδ/ERK pathway triggered by CTHRC1. Unexpectedly, osteoblast lineage-specific deletion of Tpbg downregulated Rankl expression in mouse bones and reduced both bone formation and resorption; importantly, it impaired bone mass recovery following RANKL-induced resorption, reproducing the phenotype of osteoclast-specific Cthrc1 deficiency. Thus, the binding of osteoclast-derived CTHRC1 to WAIF1 in stromal cells activates PKCδ-ERK osteoblastogenic signaling and serves as a key molecular link between bone resorption and formation during bone remodeling. © 2018 American Society for Bone and Mineral Research.

show abstract

Understanding and exploiting 5T4 oncofoetal glycoprotein expression

Cited by 27 publications

References 72 publications

Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia

Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia

Role of TPBG (Trophoblast Glycoprotein) Antigen in Human Pericyte Migratory and Angiogenic Activity

WAIF1 Is a Cell-Surface CTHRC1 Binding Protein Coupling Bone Resorption and Formation

Contact Info

Product

Resources

About