Uterine serous papillary carcinomas overexpress human trophoblast‐cell‐surface marker (trop‐2) and are highly sensitive to immunotherapy with hRS7, a humanized anti‐trop‐2 monoclonal antibody

Varughese, Joyce; Cocco, Emiliano; Bellone, Stefania; León, María; Bellone, Marta; Todeschini, Paola; Schwartz, Peter E.; Rutherford, Thomas J.; Pecorelli, Sërgio; Santin, Alessandro D.

doi:10.1002/cncr.25891

Cited by 49 publications

(46 citation statements)

References 31 publications

(60 reference statements)

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“…18 Although the relationship between high Trop-2 expression and aggressiveness of epithelial neoplasms remains unclear, it has been suggested that Trop-2, possessing cytoplasmic serine and tyrosine phosphorylation sites, might function as a cell signal transducer and regulator of tumor cell growth and increase tumor cell resistance to apoptosis. 19 Consistent with this view, Guerra et al 20 have shown that a large fraction of human cancers express a bicistronic CYCLIN D1-TROP2 mRNA chimera, acting as an oncogene able to induce aggressive tumor growth.…”

Section: Discussionmentioning

confidence: 99%

“…18 Tumors were staged according to the International Federation of Gynecologists and Obstetricians' 2010 operative staging system. Source-patient characteristics of these 3 poorly differentiated EEC cell lines (EEC-ARK-1, EEC-ARK-2, and EEC-ARK-3) are described in Table 1.…”

Section: Establishment Of Grade 3 Eec Cell Linesmentioning

confidence: 99%

“…18 Briefly, because Trop-2 is an intronless gene, the TaqMan Gene Expression Assay was designed within the exonic region. All RNA samples were then treated with TURBO DNase enzyme (TURBO DNA-free Kit; Ambion, Inc, Applied Biosystem Business, CA) to remove contaminating DNA eventually present.…”

Section: Quantitative Real-time Polymerase Chain Reactionmentioning

confidence: 99%

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Trop-2 Overexpression in Poorly Differentiated Endometrial Endometrioid Carcinoma: Implications for Immunotherapy With hRS7, a Humanized Anti–Trop-2 Monoclonal Antibody

Bignotti

Ravaggi

Romani

et al. 2011

Int J Gynecol Cancer

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Objective We evaluated the expression of human trophoblast cell-surface marker (Trop-2) in endometrial endometrioid carcinoma (EEC) and the potential application of hRS7, a humanized monoclonal anti-Trop-2 antibody, as a therapeutic agent against poorly-differentiated EEC. Methods Trop-2 expression was evaluated by immunohistochemistry in 131 EEC with different degrees of differentiation and 32 normal endometrial controls (NEC). Trop-2 expression was also evaluated by real-time polymerase-chain-reaction (qRT-PCR) and flow cytometry in 3 primary EEC cell lines derived from patients harboring poorly-differentiated EEC. Finally, sensitivity of G3 EEC cell lines to hRS7 antibody-dependent cellular-cytotoxicity (ADCC) was tested in standard 5-hours 51Cr-release assays. Results Trop-2 expression was detected in 126 of 131 (96.2%) EEC samples. Tumor tissues showed markedly increased Trop-2 positivity as compared to NEC (p=0.001). Trop-2 expression was significantly higher in all grades of EEC vs. NEC. G3 tumors displayed significantly stronger Trop-2 immunostaining compared to G1 EEC (p=0.01). High Trop-2 expression by qRT-PCR and flow cytometry was found in one G3 EEC primary cell line (EEC-ARK-1). Unlike Trop-2-negative EEC cell lines, EEC-ARK-1 was found highly sensitive to hRS7-mediated ADCC in vitro (range of killing: 33.9% to 50.6%) (p=0.004). Human serum did not significantly inhibit hRS7-mediated-cytotoxicity against EEC-ARK-1 (p= 0.773). Conclusions Trop-2 is highly expressed in EEC and its expression is significantly higher in poorly-differentiated EEC when compared to well-differentiated EEC. Primary G3 EEC overexpressing Trop-2 are highly sensitive to hRS7-mediated cytotoxicity in vitro. hRS7 may represent a novel therapeutic agent for the treatment of high-grade EEC refractory to standard treatment modalities.

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Section: Discussionmentioning

confidence: 99%

Section: Establishment Of Grade 3 Eec Cell Linesmentioning

confidence: 99%

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Trop-2 Overexpression in Poorly Differentiated Endometrial Endometrioid Carcinoma: Implications for Immunotherapy With hRS7, a Humanized Anti–Trop-2 Monoclonal Antibody

Bignotti

Ravaggi

Romani

et al. 2011

Int J Gynecol Cancer

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“…[44][45][46][47][48] ABBREVIATIONS AIRE, autoimmune regulator; CREB, cyclic AMP-responsive-element binding protein; FOXM1, forkhead box M1; Get, Grainyhead-like Abbreviations: ERa, oestrogen receptor a; (C), cytoplasmic staining; (N), nuclear staining; PgR, progesterone receptor; Rho, Spearman's correlation coefficient; P, two-tailed P-value. Significant correlations are highlighted (grey shading).…”

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confidence: 99%

The Trop-2 signalling network in cancer growth

et al. 2012

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Our findings show that upregulation of a wild-type Trop-2 has a key controlling role in human cancer growth, and that tumour development is quantitatively driven by Trop-2 expression levels. However, little is known about the regulation of expression of the TROP2 gene. Hence, we investigated the TROP2 transcription control network. TROP2 expression was shown to depend on a highly interconnected web of transcription factors: TP63/TP53L, ERG, GRHL1/Get-1 (grainyhead-like epithelial transactivator), HNF1A/TCF-1 (T-cell factor), SPI1/PU.1, WT (Wilms' tumour)1, GLIS2, AIRE (autoimmune regulator), FOXM1 (forkhead box M1) and FOXP3, with HNF4A as the major network hub. TROP2 upregulation was shown to subsequently drive the expression and activation of CREB1 (cyclic AMP-responsive-element binding protein), Jun, NF-kB, Rb, STAT1 and STAT3 through induction of the cyclin D1 and ERK (extracellular signal regulated kinase)/MEK (MAPK/ERK kinase) pathways. Growth-stimulatory signalling through NF-kB, cyclin D1 and ERK was shown to require an intact Trop-2 cytoplasmic tail. Network hubs and interacting partners are co-expressed with Trop-2 in primary human tumours, supporting a role of this signalling network in cancer growth.

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“…The cell-surface markers overexpressed in EC are the tight junction proteins, like claudin-3 and claudin-4, highly expressed in endometrioid, serous papillary, and clear-cell EC, the folate receptor a, a membrane-bound molecule, and the mesothelin, a glycosylphosphatidylinositol-linked cell-surface antigen; all of them are upregulated more frequently in serous than in endometrioid EC. The trophoblast cell-surface marker (Trop-2) is a cell-surface glycoprotein, which is highly expressed in both types of [45] EC, while epithelial cell adhesion molecule, a reliable marker for tumor-initiating cells, and L1 cell adhesion molecule (L1CAM), a key driver for tumor cell invasion and EMT, are highly expressed among serous EC [46,47].…”

Section: Scientific Rationalementioning

confidence: 99%

Emerging drugs for endometrial cancer

Amadio

Masciullo

Ferrandina

et al. 2014

Expert Opinion on Emerging Drugs

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The molecular therapies mainly discussed in this review are potential therapeutic candidates for more effective and specific treatments. In the genomic era, a deeper knowledge about molecular characteristics of cancer provides the hope for the development of better therapeutic approaches. Targeting both genetic and epigenetic alterations, attacking tumor cells using cell-surface markers overexpressed in tumor tissue, reactivating antitumor immune responses and identifying predictive biomarkers represent the emerging strategies and the major challenges.

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Uterine serous papillary carcinomas overexpress human trophoblast‐cell‐surface marker (trop‐2) and are highly sensitive to immunotherapy with hRS7, a humanized anti‐trop‐2 monoclonal antibody

Cited by 49 publications

References 31 publications

Trop-2 Overexpression in Poorly Differentiated Endometrial Endometrioid Carcinoma: Implications for Immunotherapy With hRS7, a Humanized Anti–Trop-2 Monoclonal Antibody

Trop-2 Overexpression in Poorly Differentiated Endometrial Endometrioid Carcinoma: Implications for Immunotherapy With hRS7, a Humanized Anti–Trop-2 Monoclonal Antibody

The Trop-2 signalling network in cancer growth

Emerging drugs for endometrial cancer

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