title: Overexpression of the Promigratory and Prometastatic PTK7 Receptor Is Associated with an Adverse Clinical Outcome in Colorectal Cancer.
abstract: Biomarkers and novel therapeutic targets are urgently needed in colorectal cancer (CRC). The pseudo tyrosine kinase receptor 7 (PTK7) is involved in planar cell polarity and it is deregulated in various malignancies, including CRC. Yet, little is known about its protein expression in human CRC, or about a possible correlation of its expression with clinical endpoints. Using a clinically annotated Tissue MicroArray (TMA) produced from from 192 consecutive CRC patients treated by initial surgery, we examined PTK7 expression by immunohistochemistry in tumoral tissue and matched normal mucosae, and correlated its expression with clinico-pathological features and patient outcome. PTK7 depletion by specific shRNA in HCT116 and HCT15 CRC cell lines was found to affect cell proliferation, resistance to drugs and cell migration. Tumor growth and metastatic phenotype were investigated in vivo using a xenograft mouse model of CRC cells with modulated expression of PTK7 levels. PTK7 was significantly up-regulated in CRC tissue as compared to matched healthy mucosae, and significant overexpression was found in 34% of patients. PTK7 overexpression was significantly associated with a reduced metastasis-free survival in non-metastatic patients. In HCT116 and HCT15 cells, shRNA PTK7 reduced migration but did not affect cell proliferation and resistance to drugs. In a xenograft mouse of HCT15 cells, downregulation of PTK7 led to reduced tumor growth, whereas its overexpression in PTK7-negative cancer cells led to increased metastatic events. PTK7 expression thus represents a potential prognostic biomarker and a novel therapeutic target in CRC.
authors.affiliation: CRCM, Team Cell Polarity, Cell signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Inserm, U1068, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France; CNRS, UMR7258, F-13009, Marseille, France; Department of Biopathology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Lhoumeau
authors.affiliation: CRCM, Team Cell Polarity, Cell signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Inserm, U1068, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France; CNRS, UMR7258, F-13009, Marseille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Martinez
authors.affiliation: Institut Paoli-Calmettes, Marseille, F-13009, France; Department of Biostatistics, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Boher
authors.affiliation: Institut Paoli-Calmettes, Marseille, F-13009, France; Department of Biopathology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Monges
authors.affiliation: CRCM, Team Cell Polarity, Cell signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Inserm, U1068, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France; CNRS, UMR7258, F-13009, Marseille, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Castellano
authors.affiliation: CRCM, Team Cell Polarity, Cell signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Inserm, U1068, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France; CNRS, UMR7258, F-13009, Marseille, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Goubard
authors.affiliation: CRCM, Team Cell Polarity, Cell signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Inserm, U1068, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France; CNRS, UMR7258, F-13009, Marseille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Doremus
authors.affiliation: Institut Paoli-Calmettes, Marseille, F-13009, France; Department of Biopathology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Flora
authors.initials: F
authors.lastname: Poizat
authors.affiliation: Institut Paoli-Calmettes, Marseille, F-13009, France; Department of Surgical Oncology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lelong
authors.affiliation: Institut Paoli-Calmettes, Marseille, F-13009, France; Department of Surgical Oncology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: de Chaisemartin
authors.affiliation: CRCM, Team Cell Polarity, Cell signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Inserm, U1068, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France; CNRS, UMR7258, F-13009, Marseille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Bardin
authors.affiliation: CRCM, Team Cell Polarity, Cell signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Inserm, U1068, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France; CNRS, UMR7258, F-13009, Marseille, France; Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Viens
authors.affiliation: CRCM, Team Cell Polarity, Cell signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Inserm, U1068, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France; CNRS, UMR7258, F-13009, Marseille, France; Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Raoul
authors.affiliation: CRCM, Team Cell Polarity, Cell signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Inserm, U1068, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France; CNRS, UMR7258, F-13009, Marseille, France; Department of Hematology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Prebet
authors.affiliation: CRCM, Team Cell Polarity, Cell signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Inserm, U1068, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France; CNRS, UMR7258, F-13009, Marseille, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Aurrand-Lions
authors.affiliation: CRCM, Team Cell Polarity, Cell signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Inserm, U1068, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France; CNRS, UMR7258, F-13009, Marseille, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Borg
authors.affiliation: CRCM, Team Cell Polarity, Cell signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Inserm, U1068, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France; CNRS, UMR7258, F-13009, Marseille, France; Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Gonçalves
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental; D051379:Mice; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics; D015854:Up-Regulation
chemical_list: D015815:Cell Adhesion Molecules; D034741:RNA, Small Interfering; C096905:PTK7 protein, human; D020794:Receptor Protein-Tyrosine Kinases