Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

MEF2 plays a significant role in the tumor inhibitory mechanism of encapsulated RENCA cells via EGF receptor signaling in target tumor cells

Authors: Prithy C. Martis, Atira T. Dudley, Melissa A. Bemrose, Hunter L. Gazda, Barry H. Smith, Lawrence S. Gazda

Published in: BMC Cancer | Issue 1/2018

Login to get access

Abstract

Background

Agarose encapsulated murine renal adenocarcinoma cells (RENCA macrobeads) are currently being investigated in clinical trials as a treatment for therapy-resistant metastatic colorectal cancer. We have previously demonstrated the capacity of RENCA macrobeads to produce diffusible substances that markedly inhibit the proliferation of epithelial-derived tumor cells outside the macrobead environment. This study examined the molecular mechanisms underlying the observed inhibition in targeted tumor cells exposed to RENCA macrobeads.

Methods

We evaluated changes in transcription factor responses, participating intracellular signaling pathways and the involvement of specific cellular receptors in targeted tumor cells exposed to RENCA macrobeads.

Results

Factors secreted by RENCA macrobeads significantly up-regulated the activity of the MEF2 transcription factor as well as altered the transcription of MEF2b and MEF2d isoforms in targeted tumor cells. Suppression of individual or multiple MEF2 isoforms in target tumor cells markedly reduced the growth inhibitory effects of RENCA macrobeads. Furthermore, these effects were linked to the activation of the EGF receptor as attenuation of EGFR resulted in a substantial reduction of the cancer cell growth-inhibitory effect.

Conclusions

Since interruption of the EGFR signaling cascade did not eliminate RENCA macrobead-induced growth control, our data suggests that RENCA macrobeads exert their full growth inhibitory effects through the simultaneous activation of multiple signaling pathways. In contrast to a precision medicine approach targeting single molecular abnormalities, the RENCA macrobead functions as a biological-systems therapy to re-establish regulation in a highly dysfunctional and dysregulated cancer system.
Appendix
Available only for authorised users
Literature
1.
2.
Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013;501(7467):338–45.CrossRefPubMed
3.
Haber DA, Bell DW, Sordella R, Kwak EL, Godin-Heymann N, Sharma SV, et al. Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors. Cold Spring Harb Symp Quant Biol. 2005;70:419–26.CrossRefPubMed
4.
Grigsby PW, Herr HW. Urethral tumors. In: Vogelsang NJ, Scardino, PT, Shipley WU et al., editors. Comprehensive textbook of genitourinary oncology. Baltimore: Williams & Wilkins; 1996. p. 1117–1123.
5.
Pui CH, Pei D, Campana D, Cheng C, Sandlund JT, Bowman WP, et al. A revised definition for cure of childhood acute lymphoblastic leukemia. Leukemia. 2014;28(12):2336–43.CrossRefPubMedPubMedCentral
6.
7.
Spano D, Heck C, De Antonellis P, Christofori G, Zollo M. Molecular networks that regulate cancer metastasis. Semin Cancer Biol. 2012;22(3):234–49.CrossRefPubMed
8.
Smith BH, Gazda LS, Conn BL, Jain K, Asina S, Levine DM, et al. Hydrophilic agarose macrobead cultures select for outgrowth of carcinoma cell populations that can restrict tumor growth. Cancer Res. 2011;71(3):725–35.CrossRefPubMed
9.
10.
11.
Jain K, Yang H, Cai BR, Haque B, Hurvitz AI, Diehl C, et al. Retrievable, replaceable, macroencapsulated pancreatic islet xenografts. Long-term engraftment without immunosuppression. Transplantation. 1995;59(3):319–24.CrossRefPubMed
12.
Dumpala PR, Holdcraft RW, Martis PC, Laramore MA, Parker TS, Levine DM, et al. Retention of gene expression in porcine islets after agarose encapsulation and long-term culture. Biochem Biophys Res Commun. 2016;476(4):580–5.CrossRefPubMed
13.
Gazda LS, Martis PC, Laramore MA, Bautista MA, Dudley A, Vinerean HV, et al. Treatment of agarose-agarose RENCA macrobeads with docetaxel selects for OCT4(+) cells with tumor-initiating capability. Cancer Biol Ther. 2013;14(12):1147–57.CrossRefPubMedPubMedCentral
14.
Wakeling AE, Guy SP, Woodburn JR, Ashton SE, Curry BJ, Barker AJ, et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res. 2002;62(20):5749–54.PubMed
15.
Jones HE, Goddard L, Gee JM, Hiscox S, Rubini M, Barrow D, et al. Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer. 2004;11(4):793–814.CrossRefPubMed
16.
Di Giorgio E, Clocchiatti A, Piccinin S, Sgorbissa A, Viviani G, Peruzzo P, et al. MEF2 is a converging hub for histone deacetylase 4 and phosphatidylinositol 3-kinase/Akt-induced transformation. Mol Cell Biol. 2013;33(22):4473–91.CrossRefPubMedPubMedCentral
17.
Potthoff MJ, Olson EN. MEF2: a central regulator of diverse developmental programs. Development. 2007;134(23):4131–40.CrossRefPubMed
18.
Wilker PR, Kohyama M, Sandau MM, Albring JC, Nakagawa O, Schwarz JJ, et al. Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulation. Nat Immunol. 2008;9(6):603–12.CrossRefPubMedPubMedCentral
19.
Ying CY, Dominguez-Sola D, Fabi M, Lorenz IC, Hussein S, Bansal M, et al. MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma. Nat Immunol. 2013;14(10):1084–92.CrossRefPubMedPubMedCentral
20.
Di Giorgio E, Franforte E, Cefalu S, Rossi S, Dei Tos AP, Brenca M, et al. The co-existence of transcriptional activator and transcriptional repressor MEF2 complexes influences tumor aggressiveness. PLoS Genet. 2017;13(4):e1006752.CrossRefPubMedPubMedCentral
21.
Pon JR, Marra MA. MEF2 transcription factors: developmental regulators and emerging cancer genes. Oncotarget. 2016;7(3):2297–312.CrossRefPubMed
22.
Zhang M, Truscott J, Davie J. Loss of MEF2D expression inhibits differentiation and contributes to oncogenesis in rhabdomyosarcoma cells. Mol Cancer. 2013;12(1):150.CrossRefPubMedPubMedCentral
23.
Ma L, Liu J, Liu L, Duan G, Wang Q, Xu Y, et al. Overexpression of the transcription factor MEF2D in hepatocellular carcinoma sustains malignant character by suppressing G2-M transition genes. Cancer Res. 2014;74(5):1452–62.CrossRefPubMed
24.
Di Giorgio E, Gagliostro E, Clocchiatti A, Brancolini C. The control operated by the cell cycle machinery on MEF2 stability contributes to the downregulation of CDKN1A and entry into S phase. Mol Cell Biol. 2015;35(9):1633–47.CrossRefPubMedPubMedCentral
25.
Black BL, Olson EN. Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu Rev Cell Dev Biol. 1998;14:167–96.CrossRefPubMed
26.
Aude-Garcia C, Collin-Faure V, Bausinger H, Hanau D, Rabilloud T, Lemercier C. Dual roles for MEF2A and MEF2D during human macrophage terminal differentiation and c-Jun expression. Biochem J. 2010;430(2):237–44.CrossRefPubMed
27.
Blaeser F, Ho N, Prywes R, Chatila TA. Ca(2+)-dependent gene expression mediated by MEF2 transcription factors. J Biol Chem. 2000;275(1):197–209.CrossRefPubMed
28.
She QB, Solit DB, Ye Q, O'Reilly KE, Lobo J, Rosen N. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell. 2005;8(4):287–97.CrossRefPubMedPubMedCentral
29.
Chen GJ, Karajannis MA, Newcomb EW, Zagzag D. Overexpression and activation of epidermal growth factor receptor in hemangioblastomas. J Neuro-Oncol. 2010;99(2):195–200.CrossRef
30.
Hyatt DC, Ceresa BP. Cellular localization of the activated EGFR determines its effect on cell growth in MDA-MB-468 cells. Exp Cell Res. 2008;314(18):3415–25.CrossRefPubMedPubMedCentral
31.
Chan DLH, Segelov E, Wong RS, Smith A, Herbertson RA, Li BT, et al. Epidermal growth factor receptor (EGFR) inhibitors for metastatic colorectal cancer. Cochrane Database Syst Rev. 2017;6:CD007047.PubMed
32.
Rothenberg ML, LaFleur B, Levy DE, Washington MK, Morgan-Meadows SL, Ramanathan RK, et al. Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. J Clin Oncol. 2005;23(36):9265–74.CrossRefPubMed
33.
Smith BH, Parikh T, Andrada ZP, Fahey TJ, Berman N, Wiles M, et al. First-in-human phase 1 trial of agarose beads containing murine RENCA cells in advanced solid tumors. Cancer Growth Metastasis. 2016;9:9–20.CrossRefPubMedPubMedCentral
34.
Nazarian A, Sureshbabu S, Andrada ZP, Thomas J, Arreglado A, Berman N, et al. 18F-FDG PET/CT evaluation of tumor response to the implantation of RENCA macrobeads (RMB) in phase I and II clinical trials [INDBB 10091] in advanced, treatment-resistant metastatic colorectal cancer (mCRC). J Clin Oncol. 2017;35(Suppl 15):e15046–e.CrossRef
35.
Ocean AJ, Parikh T, Berman N, Escalon J, Shah MA, Andrada Z, et al. Phase I/II trial of intraperitoneal implantation of agarose-agarose macrobeads (MB) containing mouse renal adenocarcinoma cells (RENCA) in patients (pts) with advanced colorectal cancer (CRC). J Clin Oncol. 2013;31(Suppl 15):e14517–e.
36.
Smith BH, Gazda LS, Conn BL, Jain K, Asina S, Levine DM, et al. Three-dimensional culture of mouse renal carcinoma cells in agarose macrobeads selects for a subpopulation of cells with cancer stem cell or cancer progenitor properties. Cancer Res. 2011;71(3):716–24.CrossRefPubMed
Metadata
Title
MEF2 plays a significant role in the tumor inhibitory mechanism of encapsulated RENCA cells via EGF receptor signaling in target tumor cells
Authors
Prithy C. Martis
Atira T. Dudley
Melissa A. Bemrose
Hunter L. Gazda
Barry H. Smith
Lawrence S. Gazda
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-5128-5

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue

Research article

Post-transcriptional regulation of cancer/testis antigen MAGEC2 expression by TRIM28 in tumor cells

Research article

The kallikrein-Kinin system modulates the progression of colorectal liver metastases in a mouse model

Research article

Efficacy after preoperative capecitabine and oxaliplatin (XELOX) versus docetaxel, oxaliplatin and S1 (DOS) in patients with locally advanced gastric adenocarcinoma: a propensity score matching analysis

Research article

Prognostic value of the fibrinogen/albumin ratio (FAR) in patients with operable soft tissue sarcoma

Research article

Microsatellite instability testing in colorectal cancer using the QiaXcel advanced platform

Research article

Dynamic imaging and pathological changes in pig liver after MR-guided microwave ablation
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
Image Credits