Upregulation of Trop-2 quantitatively stimulates human cancer growth

Trerotola, Marco; Cantanelli, Pamela; Guerra, Emanuela; Tripaldi, Romina; Aloisi, Anna Laura; Bonasera, Veronica; Lattanzio, Rossano; Lange, Robert D.; Weidle, Ulrich H.; Piantelli, Mauro; Alberti, Saverio

doi:10.1038/onc.2012.36

Cited by 241 publications

(262 citation statements)

References 56 publications

(68 reference statements)

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“…When inoculated in nude mice, only the MTE/ Trop-2 transfectants grew as tumors, whereas the MTE/vector cells did not produce any appreciable growth. Hence, Trop-2 confers tumorigenic capabilities to the immortalized MTE cell line, further supporting the role of Trop-2 in tumor growth (7). Strikingly, AKT inhibitors significantly reduced the growth of the Trop-2-dependent tumors (Fig.…”

Section: Trop-2 Determines Tumor Response To Akt Inhibitorsmentioning

confidence: 65%

“…Cell numbers were quantified by staining with crystal violet (7). Cell numbers were normalized against standard reference curves of 2-fold serially diluted cell samples.…”

Section: Cell Growth Assaysmentioning

confidence: 99%

“…One such a case is AKT, where considerable efforts have been dedicated to developing and testing inhibitory drugs in clinical settings, but reliable indicators of response are entirely lacking. Trop-2 is a transmembrane calcium signal transducer (2)(3)(4)(5)(6), which is overexpressed by cancer cells, and drives tumor growth (7,8) and progression (9). In this work, we dissected the Trop-2 signalosome, through high-throughput proteomic analysis.…”

Section: Introductionmentioning

confidence: 99%

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Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors

Guerra

Trerotola

Tripaldi

et al. 2016

Clinical Cancer Research

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Purpose: Inhibition of AKT is a key target area for personalized cancer medicine. However, predictive markers of response to AKT inhibitors are lacking. Correspondingly, the AKT-dependent chain of command for tumor growth, which will mediate AKTdependent therapeutic responses, remains unclear.Experimental Design: Proteomic profiling was utilized to identify nodal hubs of the Trop-2 cancer growth-driving network. Kinase-specific inhibitors were used to dissect Trop-2-dependent from Trop-2-independent pathways. In vitro assays, in vivo preclinical models, and case series of primary human breast cancers were utilized to define the mechanisms of Trop-2-driven growth and the mode of action of Trop-2-predicted AKT inhibitors.Results: Trop-2 and AKT expression was shown to be tightly coordinated in human breast cancers, with virtual overlap with AKT activation profiles at T308 and S473, consistent with functional interaction in vivo. AKT allosteric inhibitors were shown to only block the growth of Trop-2-expressing tumor cells, both in vitro and in preclinical models, being ineffective on Trop-2-null cells. Consistently, AKTtargeted siRNA only impacted on Trop-2-expressing cells. Lentiviral downregulation of endogenous Trop-2 abolished tumor response to AKT blockade, indicating Trop-2 as a mandatory activator of AKT.Conclusions: Our findings indicate that the expression of Trop-2 is a stringent predictor of tumor response to AKT inhibitors. They also support the identification of target-activatory pathways, as efficient predictors of response in precision cancer therapy. Clin Cancer Res; 22(16); 4197-205. Ó2016 AACR.

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Section: Trop-2 Determines Tumor Response To Akt Inhibitorsmentioning

confidence: 65%

“…Cell numbers were quantified by staining with crystal violet (7). Cell numbers were normalized against standard reference curves of 2-fold serially diluted cell samples.…”

Section: Cell Growth Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors

Guerra

Trerotola

Tripaldi

et al. 2016

Clinical Cancer Research

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“…Several reports indicate that, in contrast with tumor cells, somatic adult tissues show little or no Trop-2 expression, which is invariably upregulated in tumors, regardless of baseline expression in normal tissues (46,47). However, recent evidence indicates expression of Trop-2 on epithelia of several normal tissues (48). Nonetheless, expression of Trop-2 in Cynomolgus monkeys did not result in toxicities after administrations of reasonably high doses of hRS7 (humanized anti-Trop-2) conjugated with SN-38 as an antibody-drug conjugate (ADC; ref.…”

Section: Discussionmentioning

confidence: 99%

Redirected T-Cell Killing of Solid Cancers Targeted with an Anti-CD3/Trop-2–Bispecific Antibody Is Enhanced in Combination with Interferon-α

Rossi

Chang

et al. 2014

Molecular Cancer Therapeutics

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Trop-2 has limited presence on normal tissues but is highly expressed in diverse epithelial cancers. (E1)-3s is a T-cell-redirecting trivalent bispecific antibody (bsAb), comprising an anti-CD3 scFv covalently linked to a stabilized dimer of a Trop-2-targeting Fab using Dock-and-Lock. We show for the first time that bsAbmediated bidirectional trogocytosis occurs between target and T cells and involves immunologic synapses. We studied the effects of interferon-a (INFa) on (E1)-3s-mediated T-cell killing of human gastric and pancreatic cancer cell lines. T-cell activation, cytokine induction, and cytotoxicity were evaluated ex vivo using peripheral blood mononuclear cells (PBMC) or T cells with NCI-N87 gastric cancer as target cells. In vivo activity was assayed with NCI-N87 and Capan-1 (pancreatic) xenografts. In the presence of target cells and PBMCs, (E1)-3s did not cause excess cytokine production. When combined with (E1)-3s, peginterferonalfa-2a-which alone did not increase T-cell activation or raise cytokine levels over baseline-increased CD69 expression but did not significantly increase cytokine induction. (E1) 3s mediated a highly potent T-cell lysis of NCI-N87 target cells in vitro. Inclusion of peginterferonalfa-2a or a more potent form of INFa, 20 Ã -2b, significantly potentiated the activity of (E1)-3s by more than 2.5-or 7-fold, respectively. In vivo, combining peginterferonalfa-2a with (E1)-3s delayed Capan-1 growth longer than each single agent. Similarly, combination therapy delayed tumor proliferation of NCI-N87 compared with (E1)-3s or peginterferonalfa-2a single-treatment groups. (E1)-3s effectively induced T-cell-mediated killing of Trop-2-expressing pancreatic and gastric cancers, which was enhanced with INFa.

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“…Knockdown of Trop2 abrogates the growth of colon cancer cell lines and inhibits tumor initiation and progression in mice (Wang et al 2008;Trerotola et al 2012a). Recently, Trop2 was demonstrated to play dual functions in tumorigenesis-as a tumor suppressor and an oncogene (Wang et al 2008(Wang et al , 2011.…”

mentioning

confidence: 99%

Regulated proteolysis of Trop2 drives epithelial hyperplasia and stem cell self-renewal via β-catenin signaling

et al. 2012

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The cell surface protein Trop2 is expressed on immature stem/progenitor-like cells and is overexpressed in many epithelial cancers. However the biological function of Trop2 in tissue maintenance and tumorigenesis remains unclear. In this study, we demonstrate that Trop2 is a regulator of self-renewal, proliferation, and transformation. Trop2 controls these processes through a mechanism of regulated intramembrane proteolysis that leads to cleavage of Trop2, creating two products: the extracellular domain and the intracellular domain. The intracellular domain of Trop2 is released from the membrane and accumulates in the nucleus. Heightened expression of the Trop2 intracellular domain promotes stem/progenitor self-renewal through signaling via b-catenin and is sufficient to initiate precursor lesions to prostate cancer in vivo. Importantly, we demonstrate that loss of b-catenin or Trop2 loss-of-function cleavage mutants abrogates Trop2-driven self-renewal and hyperplasia in the prostate. These findings suggest that heightened expression of Trop2 is selected for in epithelial cancers to enhance the stem-like properties of self-renewal and proliferation. Defining the mechanism of Trop2 function in self-renewal and transformation is essential to identify new therapeutic strategies to block Trop2 activation in cancer.

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Upregulation of Trop-2 quantitatively stimulates human cancer growth

Cited by 241 publications

References 56 publications

Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors

Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors

Redirected T-Cell Killing of Solid Cancers Targeted with an Anti-CD3/Trop-2–Bispecific Antibody Is Enhanced in Combination with Interferon-α

Regulated proteolysis of Trop2 drives epithelial hyperplasia and stem cell self-renewal via β-catenin signaling

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