The Trop-2 signalling network in cancer growth

Guerra, Emanuela; Trerotola, Marco; Aloisi, Anna Laura; Tripaldi, Romina; Vacca, Giovanna; Sorda, Rossana La; Lattanzio, Rossano; Piantelli, Mauro; Alberti, Saverio

doi:10.1038/onc.2012.151

Cited by 117 publications

(130 citation statements)

References 52 publications

(78 reference statements)

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“…One such candidate is Trop-2 [5]–[7]. Trop-1/Ep-CAM and Trop-2 [5]–[10] are monomeric trans-membrane glycoproteins that are expressed in human epithelial cells at diverse stages of differentiation [8], [9], [11].…”

Section: Introductionmentioning

confidence: 99%

“…The signaling function of Trop-2 [7] can be activated by antibody (Ab)-mediated cross-linking of cell-surface molecules [16] or by intra-membrane cleavage [17]. On the other hand, considerable amounts of Trop-2 are retained in intracellular compartments, in a broadly heterogeneous manner in different tumors [6], which suggests that this is part of the regulation of Trop-2 function.…”

Section: Introductionmentioning

confidence: 99%

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Trop-2 Is a Determinant of Breast Cancer Survival

et al. 2014

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Trop-2 is a calcium signal transducer that drives tumor growth. Anti-Trop-2 antibodies with selective reactivity versus Trop-2 maturation stages allowed to identify two different pools of Trop-2, one localized in the cell membrane and one in the cytoplasm. Of note, membrane-localized/functional Trop-2 was found to be differentially associated with determinants of tumor aggressiveness and distinct breast cancer subgroups. These findings candidated Trop-2 states to having an impact on cancer progression. We tested this model in breast cancer. A large, consecutive human breast cancer case series (702 cases; 8 years median follow-up) was analyzed by immunohistochemistry with anti-Trop-2 antibodies with selective reactivity for cytoplasmic-retained versus functional, membrane-associated Trop-2. We show that membrane localization of Trop-2 is an unfavorable prognostic factor for overall survival (1+ versus 0 for all deaths: hazard ratio, 1.63; P = 0.04), whereas intracellular Trop-2 has a favorable impact on prognosis, with an adjusted hazard ratio for all deaths of 0.48 (high versus low; P = 0.003). A corresponding impact of intracellular Trop-2 was found on disease relapse (high versus low: hazard ratio, 0.51; P = 0.004). Altogether, we demonstrate that the Trop-2 activation states are critical determinants of tumor progression and are powerful indicators of breast cancer patients survival.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Trop-2 Is a Determinant of Breast Cancer Survival

et al. 2014

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“…It has been identified as an oncogene and its upregulation was shown to stimulate cancer growth in vitro and in vivo [103,104]. Trop-2 can activate the MAPK pathway and support a protumoral signaling network [105,106]. A possible context of Trop-2 as a metastasis-associated target was indicated by the observation that high levels of Trop-2 correlate with a higher frequency of liver metastasis in 16 CRC patients [107].…”

Section: Tumor-associated Calcium Signal Transducer 2 (Trop-2)mentioning

confidence: 96%

Molecular targets and pathways involved in liver metastasis of colorectal cancer

Weidle

Birzele

Krüger

2015

Clin Exp Metastasis

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We here summarize the current view of molecular mechanisms involved in the dissemination process of colorectal cancer cells to the liver as deduced from preclinical models. We focus on molecular aspects of the current understanding of the biology of liver metastases formation and survival, both being crucial for identification and validation of possible therapeutic targets and review the latest findings elucidating some features of the liver as a metastatic niche. In more detail, we outline the role of proteases and of major pathways such asc-MET signaling and its modulation by factors such as MACC1 and TIMP1, as well as Notch and TGFβ signaling. The relevance of these signalling pathways during tumor-stroma interactions in this context will be addressed. In addition, the functional role and validation of targets such as PRL3, Trop-2, L1CAM, S100A4, S100P, CD133, LIPC, and APOBEC3G are summarized.

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“…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%

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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The Trop-2 signalling network in cancer growth

Cited by 117 publications

References 52 publications

Trop-2 Is a Determinant of Breast Cancer Survival

Trop-2 Is a Determinant of Breast Cancer Survival

Molecular targets and pathways involved in liver metastasis of colorectal cancer

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

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