Investigating TNS4 in the Colorectal Tumor Microenvironment Using 3D Spheroid Models of Invasion

被引:7
作者
Raposo, Teresa P. [1 ,2 ]
Susanti, Susanti [1 ,2 ,3 ]
Ilyas, Mohammad [1 ,2 ]
机构
[1] Univ Nottingham, Div Canc & Stem Cells, Sch Med, Queens Med Ctr, Nottingham NG7 2UH, England
[2] Univ Nottingham, Nottingham Mol Pathol Node, Nottingham, England
[3] Univ Muhammadiyah Purwokerto, Deparment Pharmacol & Clin Pharm, Fac Pharm, Banyumas 53182, Central Java, Indonesia
基金
英国医学研究理事会;
关键词
cancer invasion; colorectal cancer; Cten; EGFR inhibitor; in vitro models; tensins; EPITHELIAL-MESENCHYMAL TRANSITION; MESSENGER-RNA EXPRESSION; CELL MOTILITY; CTEN; CANCER; FIBROBLASTS; PROGRESSION; MIGRATION; ONCOGENE; CADHERIN;
D O I
10.1002/adbi.202000031
中图分类号
TB3 [工程材料学]; R318.08 [生物材料学];
学科分类号
0805 ; 080501 ; 080502 ;
摘要
TNS4 (Tensin 4 or Cten) is a putative oncogene in colorectal cancer (CRC) with a role in regulating cell adhesion, motility, invasion, and epithelial to mesenchymal transition (EMT). The objective is to study the role of TNS4 in CRC using more realistic models of the tumor microenvironment. CRC cells expressing TdTomato protein and shTNS4/shLUC hairpin oligos are grown in 3D spheroids with and without cancer-associated fibroblasts (CAFs). Adhesiveness to collagen I and CAFs is assessed in 2D and cell proliferation, volume, and invasion are assessed in 3D conditions. The role of TNS4 knockdown in gefitinib chemosensitivity and epidermal growth factor receptor (EGFR) and Ras protein levels are also tested. In general, TNS4 knockdown increases cell proliferation in cell lines producing compact spheroids. The addition of CAFs in spheroids supports CRC cell proliferation, whereas CAFs themselves do not proliferate, but increases ECM degradation. TNS4 knockdown reduces adhesiveness and 3D invasion and disrupts EGFR signaling which results in increased sensitivity to Gefitinib. In conclusion, in a 3D spheroid model, TNS4 inhibits cell proliferation and promotes cell invasion into the ECM, possibly by adhesion to the ECM and stromal cells. TNS4 knockdown enhances sensitivity to the EGFR inhibitor gefitinib and may be helpful for Kirsten ras oncogene homolog mutant CRC patients.
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页数:10
相关论文
共 46 条
[1]   C-Terminal Tensin-Like Gene Functions as an Oncogene and Promotes Cell Motility in Pancreatic Cancer [J].
Al-Ghamdi, Saleh ;
Cachat, Julien ;
Albasri, Abdulkader ;
Ahmed, Mohammed ;
Jackson, Darryl ;
Zaitoun, Abed ;
Guppy, Naomi ;
Otto, William R. ;
Alison, Malcolm R. ;
Kindle, Karin B. ;
Ilyas, Mohammad .
PANCREAS, 2013, 42 (01) :135-140
[2]   Cten Is Targeted by Kras Signalling to Regulate Cell Motility in the Colon and Pancreas [J].
Al-Ghamdi, Saleh ;
Albasri, Abdulkader ;
Cachat, Julien ;
Ibrahem, Salih ;
Muhammad, Belal A. ;
Jackson, Darryl ;
Nateri, Abdolrahman S. ;
Kindle, Karin B. ;
Ilyas, Mohammad .
PLOS ONE, 2011, 6 (06)
[3]   Cten signals through integrin-linked kinase (ILK) and may promote metastasis in colorectal cancer [J].
Albasri, A. ;
Al-Ghamdi, S. ;
Fadhil, W. ;
Aleskandarany, M. ;
Liao, Y-C ;
Jackson, D. ;
Lobo, D. N. ;
Lo, S. H. ;
Kumari, R. ;
Durrant, L. ;
Watson, S. ;
Kindle, K. B. ;
Ilyas, M. .
ONCOGENE, 2011, 30 (26) :2997-3002
[4]  
Albasri A, 2014, ANTICANCER RES, V34, P3969
[5]   CTEN (C-terminal tensin-like), a novel oncogene overexpressed in invasive breast carcinoma of poor prognosis [J].
Albasri, Abdulkader ;
Aleskandarany, Mohammed ;
Benhasouna, Ahmed ;
Powe, Desmond G. ;
Ellis, Ian O. ;
Ilyas, Mohammad ;
Green, Andrew R. .
BREAST CANCER RESEARCH AND TREATMENT, 2011, 126 (01) :47-54
[6]   C-terminal Tensin-like (CTEN) is an oncogene which alters cell motility possibly through repression of E-cadherin in colorectal cancer [J].
Albasri, Abdulkader ;
Seth, Rashmi ;
Jackson, Darryl ;
Benhasouna, Ahmed ;
Crook, Simon ;
Nateri, Abdolrahman S. ;
Chapman, Roger ;
Ilyas, Mohammad .
JOURNAL OF PATHOLOGY, 2009, 218 (01) :57-65
[7]   Overexpression of CTEN relates to tumor malignant potential and poor outcomes of adenocarcinoma of the esophagogastric junction [J].
Aratani, Kenichi ;
Komatsu, Shuhei ;
Ichikawa, Daisuke ;
Ohashi, Takuma ;
Miyamae, Mahito ;
Okajima, Wataru ;
Imamura, Taisuke ;
Kiuchi, Jun ;
Nishibeppu, Keiji ;
Kosuga, Toshiyuki ;
Konishi, Hirotaka ;
Shiozaki, Atsushi ;
Fujiwara, Hitoshi ;
Okamoto, Kazuma ;
Tsuda, Hitoshi ;
Otsuji, Eigo .
ONCOTARGET, 2017, 8 (48) :84112-84122
[8]   Cten promotes Epithelial-Mesenchymal Transition (EMT) in colorectal cancer through stabilisation of Src [J].
Asiri, Abdulaziz ;
Toss, Michael S. ;
Raposo, Teresa Pereira ;
Akhlaq, Maham ;
Thorpe, Hannah ;
Alfahed, Abdulaziz ;
Asiri, Abutaleb ;
Ilyas, Mohammad .
PATHOLOGY INTERNATIONAL, 2019, 69 (07) :381-391
[9]   Cancer-associated fibroblasts lead tumor invasion through integrin-β3-dependent fibronectin assembly [J].
Attieh, Youmna ;
Clark, Andrew G. ;
Grass, Carina ;
Richon, Sophie ;
Pocard, Marc ;
Mariani, Pascale ;
Elkhatib, Nadia ;
Betz, Timo ;
Gurchenkov, Basile ;
Vignjevic, Danijela Matic .
JOURNAL OF CELL BIOLOGY, 2017, 216 (11) :3509-3520
[10]   Integrin α1β1 expression is controlled by c-MYC in colorectal cancer cells [J].
Boudjadi, S. ;
Carrier, J. C. ;
Groulx, J-F ;
Beaulieu, J-F .
ONCOGENE, 2016, 35 (13) :1671-1678