Inactivation of E-cadherin by Trop-2 drives colon cancer metastasis.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 105-105
Author(s):  
Saverio Alberti ◽  
Emanuela Guerra ◽  
Donato F. Altomare ◽  
Raffaella Depalo ◽  
Marco Trerotola
Keyword(s):  
Colon Cancer ◽  
Cell Adhesion ◽  
Cancer Patients ◽  
Cancer Metastasis ◽  
Colon Cancer Metastasis ◽  
Metastatic Relapse ◽  
Metastatic Spreading ◽  
E Cadherin ◽  
Cell Cell

105 Background: Tumor metastasis is the main cause of death of colon cancer patients and the biggest hurdle for cancer cure. We set to identify decisive drivers and of pivotal therapy targets for colon cancer metastasis. Methods: IHC analysis quantified the expression of target molecules in primary tumors and metastases. Cell-cell adhesion capacity was assessed in vitro and in HCT116 colon cancer cell spheroids. Pre-clinical models of orthotopic growth of KM12SM colon cancer cells and metastatic diffusion to the liver were utilized to assess metastatic spreading force of wtTrop-2 and of the constitutively-active, tail-less form of Trop-2 (Δcyto). Xenotransplant and metastasis transcriptomes were analyzed for differential induction of EMT determinants. Kaplan–Meier plots were used to illustrate survival and metastatic relapse in independent case series of colon cancer patients. Results: wtTrop-2 was shown to induce wound-healing. ΔcytoTrop-2 further increased cell migration ability. Both wtTrop-2 and ΔcytoTrop-2 induced resistance to apoptosis in vitro and in vivo. wtTrop-2 strikingly increased the metastatic capacity of KM12SM cells, raising metastasis rates from 45% for control cells to 90% for wtTrop-2 transfectants. The constitutively-active ΔcytoTrop-2 further boosted metastatic spreading, with metastatic livers reaching up to four times their normal size. Cancer metastases revealed high levels of E-cadherin, in the absence of transcriptional down-regulation. EMT transcription factors were largely missing from Trop-2-activated cells. Rather, binding to Trop-2 was shown to cause the release of E-cadherin from the cytoskeleton, loss of cell-cell adhesion and activation of β-catenin. This global, Trop-2/E-cadherin/β-catenin-driven pro-metastatic program was recapitulated in colon cancer patients and was shown to impact on colon cancer metastatic relapse and overall patient survival. Conclusions: We identify Trop-2-driven functional inactivation of E-cadherin as a widespread driver of metastatic diffusion in colon cancer, opening novel avenues for personalized diagnostic procedures and anti-cancer therapies. [Table: see text]

Trop-2 inactivates E-cadherin and drives colon cancer metastasis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15576-e15576
Author(s):  
Saverio Alberti ◽  
Emanuela Guerra ◽  
Donato F. Altomare ◽  
Raffaella Depalo ◽  
Marco Trerotola
Keyword(s):  
Colon Cancer ◽  
Cell Adhesion ◽  
Cancer Metastasis ◽  
Case Series ◽  
Cancer Therapies ◽  
Primary Tumors ◽  
Metastatic Relapse ◽  
E Cadherin ◽  
Cell Cell

e15576 Background: Metastatic diffusion is the biggest hurdle for colon cancer (CRC) cure and the identification of decisive drivers of CRC metastasis is an urgent need in CRC care. Methods: The expression of target molecules in primary tumors and metastases was systematically assessed by DNA array and IHC analysis. Cell-cell adhesion capacity was quantified in 2D cell cultures and in HCT116 CRC cell spheroids. Pro-metastatic impact of wtTrop-2 and activated, tail-less Trop-2 (Δcyto) was assessed in vivo in orthotopic diffusion models of KM12SM CRC cells. Primary CRC and metastasis transcriptomes were analyzed for differential induction of EMT determinants. Kaplan–Meier plots were used to illustrate survival and metastatic relapse in independent case series of CRC patients. Results: Trop-2 was identified as uniquely upregulated in CRC models by transcriptome analysis. wtTrop-2 and ΔcytoTrop-2 were shown to induce cell migration, wound-healing and resistance to apoptosis induction . wtTrop-2 increased the metastatic capacity of KM12SM cells, raising metastasis diffusion from 45% for control cells to 90% for wtTrop-2 transfectants. The constitutively-active ΔcytoTrop-2 further boosted metastatic spreading, with metastatic livers reaching up to four times their normal size. Constitutive high expression of E-cadherin was revealed in cancer metastases. No evidence was obtained for transcriptional down-regulation of epithelial differentiation biomarkers. No induction of EMT transcription factors was observed in Trop-2-activated cells. Trop-2 tightly bound E-cadherin and caused its release from the cytoskeleton, for loss of cell-cell adhesion and activation of β-catenin. The Trop-2/E-cadherin/β-catenin-driven pro-metastatic program was recapitulated in CRC patients and was shown to impact on CRC metastatic relapse and overall patient survival. Conclusions: We identify Trop-2-driven functional inactivation of E-cadherin as a key driver of metastatic diffusion in CRC. These findings may pave the way for novel multi-marker personalized diagnostics and anti-cancer therapies. [Table: see text]

scholarly journals Exosomal lncRNA PVT1/VEGFA Axis Promotes Colon Cancer Metastasis and Stemness by Downregulation of Tumor Suppressor miR-152-3p

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Shiue-Wei Lai ◽  
Ming-Yao Chen ◽  
Oluwaseun Adebayo Bamodu ◽  
Ming-Shou Hsieh ◽  
Ting-Yi Huang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Growth Factor ◽  
Cell Lines ◽  
Distant Metastasis ◽  
Cancer Metastasis ◽  
Lovo Cell ◽  
Promoting Effect ◽  
Colon Cancer Metastasis

Background. Treating advanced colon cancer remains challenging in clinical settings because of the development of drug resistance and distant metastasis. Mechanisms underlying the metastasis of colon cancer are complex and unclear. Methods. Computational analysis was performed to determine genes associated with the exosomal long noncoding (lncRNA) plasmacytoma variant translocation 1 (PVT1)/vascular endothelial growth factor A (VEGFA) axis in patients with colon cancer. The biological importance of the exosomal lncRNA PVT1/VEGFA axis was examined in vitro by using HCT116 and LoVo cell lines and in vivo by using a patient-derived xenograft (PDX) mouse model through knockdown (by silencing of PVT1) and overexpression (by adding serum exosomes isolated from patients with distant metastasis (M-exo)). Results. The in silico analysis demonstrated that PVT1 overexpression was associated with poor prognosis and increased expression of metastatic markers such as VEGFA and epidermal growth factor receptor (EGFR). This finding was further validated in a small cohort of patients with colon cancer in whom increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. M-exo were enriched with PVT1 and VEGFA, and both migratory and invasive abilities of colon cancer cell lines increased when they were cocultured with M-exo. The metastasis-promoting effect was accompanied by increased expression of Twist1, vimentin, and MMP2. M-exo promoted metastasis in PDX mice. In vitro silencing of PVT1 reduced colon tumorigenic properties including migratory, invasive, colony forming, and tumorsphere generation abilities. Further analysis revealed that PVT1, VEGFA, and EGFR interact with and are regulated by miR-152-3p. Increased miR-152-3p expression reduced tumorigenesis, where increased tumorigenesis was observed when miR-152-3p expression was downregulated. Conclusion. Exosomal PVT1 promotes colon cancer metastasis through its association with EGFR and VEGFA expression. miR-152-3p targets both PVT1 and VEGFA, and this regulatory pathway can be explored for drug development and as a prognostic biomarker.

RNA interference of osteopontin inhibits in vitro and in vivo colon cancer metastasis

2004 ◽  
Vol 121 (2) ◽  
pp. 300
Author(s):  
P.Y. Wai ◽  
Z. Mi ◽  
H. Guo ◽  
S. Sarraf-Yazdi ◽  
B. Clary ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Rna Interference ◽  
Cancer Metastasis ◽  
Colon Cancer Metastasis

Role of endothelin a receptor in colon cancer metastasis: In vitro and in vivo evidence

2013 ◽  
Vol 53 (S1) ◽  
pp. E85-E91 ◽  
Author(s):  
Shaolin Nie ◽  
Jumei Zhou ◽  
Fei Bai ◽  
Bonian Jiang ◽  
Juying Chen ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Metastasis ◽  
Colon Cancer Metastasis ◽  
Endothelin A Receptor ◽  
Endothelin A

scholarly journals Biogenesis of Polarized Epithelial Cells During Kidney Development In Situ: Roles of E-Cadherin–mediated Cell–Cell Adhesion and Membrane Cytoskeleton Organization

1998 ◽  
Vol 9 (11) ◽  
pp. 3161-3177 ◽  
Author(s):  
Peter A. Piepenhagen ◽  
W. James Nelson
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Kidney Development ◽  
Lateral Membrane ◽  
Membrane Cytoskeleton ◽  
Triton X ◽  
E Cadherin ◽  
Cell Cell

Organization of proteins into structurally and functionally distinct plasma membrane domains is an essential characteristic of polarized epithelial cells. Based on studies with cultured kidney cells, we have hypothesized that a mechanism for restricting Na/K-ATPase to the basal-lateral membrane involves E-cadherin–mediated cell–cell adhesion and integration of Na/K-ATPase into the Triton X-100–insoluble ankyrin- and spectrin-based membrane cytoskeleton. In this study, we examined the relevance of these in vitro observations to the generation of epithelial cell polarity in vivo during mouse kidney development. Using differential detergent extraction, immunoblotting, and immunofluorescence histochemistry, we demonstrate the following. First, expression of the 220-kDa splice variant of ankyrin-3 correlates with the development of resistance to Triton X-100 extraction for Na/K-ATPase, E-cadherin, and catenins and precedes maximal accumulation of Na/K-ATPase. Second, expression of the 190-kDa slice variant of ankyrin-3 correlates with maximal accumulation of Na/K-ATPase. Third, Na/K-ATPase, ankyrin-3, and fodrin specifically colocalize at the basal-lateral plasma membrane of all epithelial cells in which they are expressed and during all stages of nephrogenesis. Fourth, the relative immunofluorescence staining intensities of Na/K-ATPase, ankyrin-3, and fodrin become more similar during development until they are essentially identical in adult kidney. Thus, renal epithelial cells in vivo regulate the accumulation of E-cadherin–mediated adherens junctions, the membrane cytoskeleton, and Na/K-ATPase through sequential protein expression and assembly on the basal-lateral membrane. These results are consistent with a mechanism in which generation and maintenance of polarized distributions of these proteins in vivo and in vitro involve cell–cell adhesion, assembly of the membrane cytoskeleton complex, and concomitant integration and retention of Na/K-ATPase in this complex.

scholarly journals RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth

2017 ◽  
Vol 114 (48) ◽  
pp. 12791-12796 ◽  
Author(s):  
Ke Yao ◽  
Cong Peng ◽  
Yuwen Zhang ◽  
Tatyana A. Zykova ◽  
Mee-Hyun Lee ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Liver Metastasis ◽  
Cancer Metastasis ◽  
Mononuclear Cells ◽  
Kinase Assay ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
Colon Cancer Metastasis ◽  
Ribosomal S6 Kinase

Metastasis is a major cause of cancer-related deaths. Approximately 80% of patients with colorectal cancer develop liver metastasis and 20% develop lung metastasis. We found that at different stages of colon cancer, IFNγ secretion from peripheral blood mononuclear cells was decreased compared with healthy controls. The ribosomal S6 kinase (RSK) family of kinases has multiple cellular functions, and we examined their roles in this observed IFNγ decrease. Flow cytometry analysis of wild-type (WT) and RSK2 knockout (KO) mice revealed significantly lower levels of IFNγ in the RSK2 KO mice compared with the WT mice. Since IFNγ is a component of immunity, which contributes to protection against metastatic carcinomas, we conducted a colon cancer liver metastasis experiment. We found significantly greater metastasis in RSK2 KO mice compared with WT mice. Transcription factor T-bet can directly activate Ifnγ gene transcription. In vitro kinase assay results showed that RSK2 phosphorylated T-bet at serines 498 and 502. We show that phosphorylation of T-bet by RSK2 is required for IFNγ expression, because knockdown of RSK2 expression or overexpression of mutant T-bet reduces IFNγ mRNA expression. To verify the function of the phosphorylation sites, we overexpressed a constitutively active mutant T-bet (S498E/S502E) in bone marrow. Mutant T-bet restored the IFNγ mRNA levels and dramatically reduced the metastasis rate in these mice. Overall, these results indicate that phosphorylation of T-bet is required for the inhibition of colon cancer metastasis and growth through a positive regulation of RSK2/T-bet/IFNγ signaling.

‘MCC’ protein interacts with E-cadherin and β-catenin strengthening cell–cell adhesion of HCT116 colon cancer cells

Oncogene ◽  
2017 ◽  
Vol 37 (5) ◽  
pp. 663-672 ◽  
Author(s):  
F A Benthani ◽  
D Herrmann ◽  
P N Tran ◽  
L Pangon ◽  
M C Lucas ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Adhesion ◽  
Cancer Cells ◽  
Colon Cancer Cells ◽  
E Cadherin ◽  
Cell Cell

Regulation of the cell-cell adhesion protein, E-cadherin, in dog and human thyrocytes in vitro.

Endocrinology ◽  
1995 ◽  
Vol 136 (7) ◽  
pp. 3113-3119 ◽  
Author(s):  
G Brabant ◽  
C Hoang-Vu ◽  
J Behrends ◽  
Y Cetin ◽  
E Pötter ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adhesion Protein ◽  
Cell Adhesion Protein ◽  
E Cadherin ◽  
Cell Cell
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