Top

Published in:

01-06-2013 | PRECLINICAL STUDIES

Expression of matrix macromolecules and functional properties of EGF-responsive colon cancer cells are inhibited by panitumumab

Authors: Ch. Gialeli, A. D. Theocharis, D. Kletsas, G. N. Tzanakakis, N. K. Karamanos

Published in: Investigational New Drugs | Issue 3/2013

Summary

The epidermal growth factor receptor (EGFR) is a member of the HER family receptors and its activation induced by its natural ligand EGF results in colon cancer growth and progression. Panitumumab (pmAb) is a fully human IgG2 anti-EGFR antibody that blocks the EGFR actions. In the present study, we evaluated the effects of pmAb on the EGF-mediated cellular responses in a panel of colon cancer cells (HCT-8, HT-29, DLD-1 and HCT-116). HCT-1116 and DLD-1 cells showed no significant EGF-dependent cell proliferation; HT-29 and HCT-8 exhibited an EGF-dependent proliferation, with HCT-8 cells to be the most responsive with significant EGFR phosphorylation upon treatment with EGF. The effects of pmAb were then evaluated in the most EGF-responsive cells, HCT-8. In that respect, pmAb impedes the signaling cascade mediated by EGFR intracellular phosphorylation and activity of focal adhesion kinase (FAK) as well as the EGF-induced invasive and migratory potential of colon cancer cells. At the level of matrix effectors implicated in colon cancer progression we report that pmAb is a potent inhibitor of constitute and EGF-mediated gene expression of certain matrix effectors, such as membrane-type 1 metalloproteinase (MT1-MMP), extracellular metalloproteinases inducer (EMMPRIN), urokinase plasminogen activator (uPA) and syndecan-4. The obtained data demonstrated that pmAb is a specific blocker of EGF-mediated EGFR activation, resulting in a significant inhibition of colon cancer cell proliferation in early stages of growth, migration and invasiveness as well as of matrix effector implicated in cancer progression.

Leserer M, Gschwind A, Ullrich A (2000) Epidermal growth factor receptor signal transactivation. IUBMB Life 49(5):405–409. doi:10.1080/152165400410254 PubMedCrossRef

Spano JP, Fagard R, Soria JC, Rixe O, Khayat D, Milano G (2005) Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspectives. Ann Oncol 16(2):189–194. doi:10.1093/annonc/mdi057 PubMedCrossRef

Yarden Y (2001) The EGFR family and its ligands in human cancer: signaling mechanisms and opportunities. Eur J Cancer 37(4):S3–S8. doi:10.1016/S0959-8049(01)00230-1 PubMedCrossRef

Iozzo RV, Karamanos N (2010) Proteoglycans in health and disease: emerging concepts and future directions. FEBS J 277(19):3863. doi:10.1111/j.1742-4658.2010.07796.x PubMedCrossRef

Nagase H, Karamanos N (2011) Metalloproteinases in health and disease: challenges and the future prospects. FEBS J 278(1):1. doi:10.1111/j.1742-4658.2010.07917.x PubMedCrossRef

Hascall V, Karamanos N (2011) Regulatory roles of hyaluronan in health and disease. FEBS J 278(9):1411. doi:10.1111/j.1742-4658.2011.08068.x PubMedCrossRef

Woods A, Couchman JR (2001) Syndecan 4 and focal adhesion function. Curr Opin Cell Biol 13:578–583. doi:10.1016/S0955-0674(00)00254-4 PubMedCrossRef

Gialeli C, Theocharis AD, Karamanos NK (2011) Matrix metalloproteinases in health and disease: roles in cancer progression and their pharmacological targeting. FEBS J 278:16–27. doi:10.1111/j.1742-4658.2010.07919.x PubMedCrossRef

Stahtea NX, Roussidis AE, Kanakis I, Tzanakakis GN, Chalkiadakis G, Mavroudis D, Kletsas D, Karamanos NK (2007) Imatinib inhibits colorectal cancer cell growth and suppresses stromal-induced growth stimulation, MT1-MMP expression and pro-MMP-2 activation. Int J Cancer 121(12):2808–2814. doi:10.1002/ijc.23029 PubMedCrossRef

10.

Jin JS, Wu CY, Lin YF, Wang JY, Yu CP, Sheu LF, Chiang H, Tsai WC, Lee WH (2006) Higher expression of epidermal growth factor receptor is associated with extracellular matrix metalloprotease inducer in colorectal adenocarcinoma: tissue microarray analysis of immunostaining score with clinicopathological parameters. Dis Markers 22(5–6):309–316PubMed

11.

Menashi S, Serova M, Ma L, Vignot S, Mourah S, Calvo F (2003) Regulation of extracellular matrix metalloproteinase inducer and matrix metalloproteinase expression by amphiregulin in transformed human breast epithelial cells. Cancer Res 63:7575–7580PubMed

12.

Morgan H, Hill PA (2005) Human breast cancer cell-mediated bone collagen degradation requires plasminogen activation and matrix metalloproteinase activity. Canc Cell Int 5:1. doi:10.1186/1475-2867-5-1 CrossRef

13.

Wu M, Rivkin A, Pham T (2008) Panitumumab: human monoclonal antibody against epidermal growth factor receptors for the treatment of metastatic colorectal cancer. Clin Therap 30(1):14–30. doi:10.1016/j.clinthera.2008.01.014 CrossRef

14.

Van Custem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664. doi:10.1200/JCO.2006.08.1620 CrossRef

15.

Gialeli C, Kletsas D, Mavroudis D, Kalofonos HP, Tzanakakis GN, Karamanos NK (2009) Targeting epidermal growth factor receptor in solid tumors: critical evaluation of the biological importance of therapeutic monoclonal antibodies. Curr Med Chem 16:3797–3804. doi:10.2174/092986709789177984 PubMedCrossRef

16.

Nikitovic D, Pratsinis H, Berdiaki A, Gialeli C, Kletsas D, Tzanakakis GN (2012) Growth factor signaling and extracellular matrix. In: Karamanos NK (ed) Extracellular matrix: pathobiology and signaling. De Gruyter, Berlin, pp 741–753

17.

Balin-Gauthier D, Delord JP, Rochaix P, Mallard V, Thomas F, Hennebelle I, Bugat R, Canal P, Allal C (2006) In vivo and in vitro antitumor activity of Oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR. Canc Chemother Pharmacol 57(6):709–718. doi:10.1007/s00280-005-0123-3 CrossRef

18.

Jhawer M, Goel S, Wilson AJ, Montagna C, Ling YH, Byun DS, Nasser S, Arango D, Shin J, Klampfer L, Augenlicht LH, Perez-Soler R, Mariadason JM (2008) PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68(6):1953–1961. doi:10.1158/0008-5472.CAN-07-5659 PubMedCrossRef

19.

Siddiqui AD, Piperdi B (2010) KRAS mutation in colon cancer: a marker of resistance to EGFR-I therapy. Ann Surg Oncol 17(4):1168–1176. doi:10.1245/s10434-009-0811-z PubMedCrossRef

20.

Fears CY, Woods A (2006) The role of syndecans in disease and wound healing. Matrix Biol 25:443–456. doi:10.1016/j.matbio.2006.07.003 PubMedCrossRef

21.

You B, Chen EX (2012) Anti-EGFR monoclonal antibodies for treatment of colorectal cancers: development of cetuximab and panitumumab. J Clin Pharmacol 52:128–155CrossRef

22.

Peeters M, Price TJ, Cervantes A et al (2010) Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 28(31):4706–4713. doi:10.1177/0091270010395940 PubMedCrossRef

23.

Douillard JY, Siena S, Cassidy J et al (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28(31):4697–4705. doi:10.1200/JCO.2009.27.4860 PubMedCrossRef

24.

Amado RG, Wolf M, Peeters M et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26(10):1626–1634. doi:10.1200/JCO.2007.14.7116 PubMedCrossRef

25.

Schwock J, Dhani N, Hedley DW (2010) Targeting focal adhesion kinase signaling in tumor growth and metastasis. Expert Opin Ther Targets 14(1):77–94. doi:10.1517/14728220903460340 PubMedCrossRef

26.

Hauck C, Sieg D, Hsia D, Loftus J, Gaarde W, Monia BP, Schlaepfer DD (2001) Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. Cancer Res 61:7079. doi:10.1242/jcs.00373 PubMed

27.

Lu Z, Jiang G, Blume-Jensen P, Hunter T (2001) Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase. Mol Cell Biol 21(12):4016. doi:10.1128/MCB.21.12.4016-4031.2001 PubMedCrossRef

28.

Sounni NE, Noel A (2005) Membrane type-matrix metalloproteinases and tumor progression. Biochimie 87:329–342. doi:10.1016/j.biochi.2004.07.012 PubMedCrossRef

29.

Weaver MA (2006) Invadopodia: specialized cell structures of cancer invasion. Clin Exp Metast 23:97–105. doi:10.1007/s10585-006-9014-1 CrossRef

30.

Zarrabi K, Dufour A, Li J, Kuscu C, Pulkoski-Gross A, Zhi J, Hu Y, Sampson NS, Zucker S, Cao J (2011) Inhibition of matrix metalloproteinase 14 (MMP-14)-mediated cancer cell migration. J Biol Chem 286(38):33167–33177. doi:10.1074/jbc.M111.256644 PubMedCrossRef

31.

Jo M, Thomas KS, O’Donnell DM, Gonias SL (2003) Epidermal growth factor receptor-dependent and –independent cell-signaling pathways originating from the urokinase receptor. J Biol Chem 278:1642–1646. doi:10.1074/jbc.M210877200 PubMedCrossRef

32.

Liu D, Ghiso JA, Estrada Y, Ossowski L (2002) EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Canc Cell 1:445–457. doi:10.1016/S1535-6108(02)00072-7 CrossRef

Title: Expression of matrix macromolecules and functional properties of EGF-responsive colon cancer cells are inhibited by panitumumab
Authors: Ch. Gialeli
A. D. Theocharis
D. Kletsas
G. N. Tzanakakis
N. K. Karamanos
Publication date: 01-06-2013
Publisher: Springer US
Published in: Investigational New Drugs / Issue 3/2013
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-012-9875-x

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Summary

Please log in to get access to this content

Other articles of this Issue 3/2013

A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral foretinib, a multi-kinase inhibitor, in patients with solid tumors

Erratum to: Effect of the drug transporters ABCG2, Abcg2, ABCB1 and ABCC2 on the disposition, brain accumulation and myelotoxicity of the aurora kinase B inhibitor barasertib and its more active form barasertib-hydroxy-QPA

The novel antiangiogenic VJ115 inhibits the NADH oxidase ENOX1 and cytoskeleton-remodeling proteins

A pilot study for the early assessment of the effects of BMS-754807 plus gefitinib in an H292 tumor model by [18F]fluorothymidine-positron emission tomography

A phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors

Erratum to: Phase I study of PM00104 (Zalypsis®) administered as a 1-hour weekly infusion resting every fourth week in patients with advanced solid tumors

Keynote webinar | Spotlight on antibody–drug conjugates in cancer