Okayama University Research: Insights Into Mechanisms Governing the Resistance to the Anti-Cancer Medication Cetuximab

Tuesday, September 25, 2018 Research News
Email Print This Page Comment bookmark
Font : A-A+

OKAYAMA, Japan, September 25, 2018 /PRNewswire/ --

Okayama University researchers report in Biochemical and Biophysical

Research Communications that the anti-cancer drug cetuximab is released with vesicles from cancer cells, findings that may enable the development of strategies to improve the effectiveness of cetuximab for treating head and neck cancer.

    

(Photo: https://mma.prnewswire.com/media/749271/Okayama_EGF.jpg )

Head and neck squamous cell carcinoma (HNSCC) is a type of cancer derived from specific kinds of cells: squamous cells in the mouth, nose, and throat. An important signaling pathway that promotes the survival and growth of these cancer cells is initiated by the protein EGF when it binds to its receptor EGFR. Research has shown that risk factors for HNSCC such as cigarette smoking can increase the secretion of EGF and in turn simulate this pathway.

Cetuximab is a monoclonal antibody acting against EGFR that is widely used to treat HNSCC. This means that cetuximab binds to EGFR with greater affinity than EGF but will not let the subsequent pathway to function. However, recently, the emergence of resistance to cetuximab has been discovered but its mechanism is not clear.

The prime feature of oral squamous cell carcinoma (OSCC) cells is their ability to secrete different sized extracellular vesicles (EVs) - fluid-filled sacs containing a variety of cellular constituents. When EVs comprise of EGFR they are referred to as EGFR-EVs. Another feature of OSCC cells is their ability to undergo an epithelial to mesenchymal transition (EMT), which gives these cells the enhanced mobility that cancer cells require to migrate and invade healthy tissues. Here, Assistant Professor Takanori Eguchi and colleagues report on their study to understand the effects of cetuximab on all these features of OSCC when induced by EGF.

The researchers first looked at effects of cetuximab on EGF-driven EMT in OSCC cells by analyzing markers of EMT. Their results showed that while EGF binding resulted in EMT initiation, only a partial suppression of EMT was observed after cetuximab treatment. Next, the effects of EGF and cetuximab on the secretion of EGFR-EVs were investigated. Using sophisticated microscopy techniques, the team studied the structure and components of the EVs. While EGF increased this secretion, cetuximab did not reduce it even partially but rather promoted EGFR-EV secretion. In fact, high levels of secreted EFGR-EVs were seen when co-stimulation with EGF and cetuximab carried out. If EGFR levels are increased in the vesicles, it makes sense that they are found in smaller amounts inside the cell, suggesting that this is a method by which cells clear excess EGFR out.

Based on this interpretation of their findings, the researchers then studied if the secreted EGFR-EVs contained cetuximab. Indeed, Western blot analysis of carefully prepared EVs revealed the presence of cetuximab, suggesting the possible mechanism by which OSCC cells get rid of cetuximab and develop resistance to its effects. Lastly, to check that genetic alterations in the cell line used were not responsible for the results the researchers investigated the panel of genes present but did not find any major aberrations.

The researchers conclude that "OSCC derived EVs trigger the secretion of a molecularly targeted antibody drug cetuximab, whose secretion could be a novel mechanism underlying antibody drug resistance in OSCC". Preventing this secretion might be a promising strategy in reducing cetuximab resistance, thereby increasing its effectiveness against HNSCC.

Background 

Receptors, effectors, and antibodies 

Receptors, such as EGFR, are proteins found on the cell surface or inside the cell. Receptors are usually activated when ligands such as proteins and chemicals bind to them. Upon activation, a chemical change usually ensues, followed by a cellular response. For example, when EGF binds EGFR, it results in dimerization of EGFR, followed by activation of signals inside the cell that are ultimately responsible for the cancer cell proliferation.

Antibodies are proteins usually produced in the plasma of organisms in response to foreign pathogens or antigens. Antibodies can neutralize pathogens by recognizing and binding to specific proteins on the pathogen. An extension of this concept is used in the production of monoclonal antibodies such as cetuximab. Monoclonal antibodies against a specific protein are usually produced and derived from animals. In this case, EGFR was the protein used to generate cetuximab, the antibody that can bind and neutralize it. Monoclonal antibodies are highly specific in nature.

Squamous cells and epithelial to mesenchymal transition (EMT) 

Squamous cells are flat cells found primarily in the outer layer of the skin and some inner linings such as in the tongue, oral mucosa, and throat. Squamous cells can be classified as epithelial cells, the epithelium being the layer that forms the surface of the body. EMT is a cellular phenomenon by which epithelial cells switch to the shape and characteristic of mesenchymal cells; those that can be transformed into a variety of different cells. EMT is therefore a process that pre-cancer cells such as in OSCC cells undergo, to migrate and attack non-cancerous cells.

Reference 

Toshifumi Fujiwara, Takanori Eguchi, Chiharu Sogawa, Kisho Ono, Jun Murakami, Soichiro Ibaragi, Jun-ichi Asaumi, Kuniaki Okamoto, Stuart K. Calderwood, Ken-ichi Kozaki. Anti-EGFR antibody cetuximab is secreted by oral squamous cell carcinoma and alters EGF-driven mesenchymal transition. Biochemical and Biophysical Research Communication, 2018 Sep 10;503(3):1267-1272.

DOI: 10.1016/j.bbrc.2018.07.035

https://doi.org/10.1016/j.bbrc.2018.07.035

Reference (Okayama Univ. e-Bulletin): Assistant Professor Eguchi's team 

OU-MRU Vol.51?Potential of 3D nanoenvironments for experimental cancer

PRESS RELEASE(February 2018)?The Production of Organoids with Cancer Stem-like Models Leads to a Successful Living Organism Analysis. Discovery of Organoids with Cancer Cells Efficiently Accumulating and Secreting Protein

PRESS RELEASE(May 2018)?Successful inhibition of cancer invasion and metastasis by targeting the PEX isoform / MMP3

PRESS RELEASE(May 2018)?Discovery and targeting of cancer progression factors from exosomes secreted by oral cancer cells

 

Okayama University Medical Research Updates ?OU-MRU?

Vol.1?Innovative non-invasive 'liquid biopsy' method to capture circulating tumor cells from blood samples for genetic testing

Vol.2?Ensuring a cool recovery from cardiac arrest

Vol.3?Organ regeneration research leaps forward

Vol.4?Cardiac mechanosensitive integrator

Vol.5?Cell injections get to the heart of congenital defects

Vol.6?Fourth key molecule identified in bone development

Vol.7?Anticancer virus solution provides an alternative to surgery

Vol.8?Light-responsive dye stimulates sight in genetically blind patients

Vol.9?Diabetes drug helps towards immunity against cancer

Vol.10?Enzyme-inhibitors treat drug-resistant epilepsy

Vol.11?Compound-protein combination shows promise for arthritis treatment

Vol.12?Molecular features of the circadian clock system in fruit flies

Vol.13?Peptide directs artificial tissue growth

Vol.14?Simplified boron compound may treat brain tumours

Vol.15?Metamaterial absorbers for infrared inspection technologies

Vol.16?Epigenetics research traces how crickets restore lost limbs

Vol.17?Cell research shows pathway for suppressing hepatitis B virus

Vol.18?Therapeutic protein targets liver disease

Vol.19?Study links signalling protein to osteoarthritis

Vol.20?Lack of enzyme promotes fatty liver disease in thin patients

Vol.21?Combined gene transduction and light therapy targets gastric cancer

Vol.22?Medical supportive device for hemodialysis catheter puncture

Vol.23?Development of low cost oral inactivated vaccines for dysentery

Vol.24?Sticky molecules to tackle obesity and diabetes

Vol.25?Self-administered aroma foot massage may reduce symptoms of anxiety

Vol.26?Protein for preventing heart failure

Vol.27?Keeping cells in shape to fight sepsis

Vol.28?Viral-based therapy for bone cancer

Vol.29?Photoreactive compound allows protein synthesis control with light

Vol.30?Cancer stem cells' role in tumor growth revealed

Vol.31?Prevention of RNA virus replication

Vol.32?Enzyme target for slowing bladder cancer invasion

Vol.33?Attacking tumors from the inside

Vol.34?Novel mouse model for studying pancreatic cancer

Vol.35?Potential cause of Lafora disease revealed

Vol.36?Overloading of protein localization triggers cellular defects

Vol.37?Protein dosage compensation mechanism unravelled

Vol.38?Bioengineered tooth restoration in a large mammal

Vol.39?Successful test of retinal prosthesis implanted in rats

Vol.40?Antibodies prolong seizure latency in epileptic mice

Vol.41?Inorganic biomaterials for soft-tissue adhesion

Vol.42?Potential drug for treating chronic pain with few side effects

Vol.43?Potential origin of cancer-associated cells revealed

Vol.44?Protection from plant extracts

Vol.45?Link between biological-clock disturbance and brain dysfunction uncovered

Vol.46?New method for suppressing lung cancer oncogene

Vol.47?Candidate genes for eye misalignment identified

Vol.48?Nanotechnology-based approach to cancer virotherapy

Vol.49?Cell membrane as material for bone formation

Vol.50?Iron removal as a potential cancer therapy

Vol.51?Potential of 3D nanoenvironments for experimental cancer

Vol.52?A protein found on the surface of cells plays an integral role in tumor growth and sustenance

Vol.53?Successful implantation and testing of retinal prosthesis in monkey eyes with retinal degeneration

Vol.54?Measuring ion concentration in solutions for clinical and environmental research

Vol.55?Diabetic kidney disease: new biomarkers improve the prediction of the renal prognosis

Vol.56?New device for assisting accurate hemodialysis catheter placement

Vol.57?Possible link between excess chewing muscle activity and dental disease

About Okayama University 

Okayama University is one of the largest comprehensive universities in Japan with roots going back to the Medical Training Place sponsored by the Lord of Okayama and established in 1870. Now with 1,300 faculty and 13,000 students, the University offers courses in specialties ranging from medicine and pharmacy to humanities and physical sciences. Okayama University is located in the heart of Japan approximately 3 hours west of Tokyo by Shinkansen.

Website: http://www.okayama-u.ac.jp/index_e.html

Correspondence to Assistant Professor Takanori Eguchi, D.D.S., Ph.D. Department of Dental Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Shikata-cho 2-5-1, Okayama city, Okayama 700-8558, Japan E-mail: eguchi@okayama-u.ac.jp https://scholar.google.com/citations?hl=en&user=d37h9nQAAAAJ&view_op=list_works&sortby=pubdate Further information Okayama University Public Relations and Information Strategy 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan E-mail: www-adm@adm.okayama-u.ac.jp Website: http://www.okayama-u.ac.jp/index_e.html Okayama Univ. e-Bulletin: http://www.okayama-u.ac.jp/user/kouhou/ebulletin/ About Okayama University (YouTube): https://www.youtube.com/watch?v=iDL1coqPRYI Okayama University Image Movie (YouTube): https://www.youtube.com/watch?v=KU3hOIXS5kk

SOURCE Okayama University



Post your Comments

Comments should be on the topic and should not be abusive. The editorial team reserves the right to review and moderate the comments posted on the site.
* Your comment can be maximum of 2500 characters
I agree to the terms and conditions

News A - Z

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

News Search

Medindia Newsletters

Subscribe to our Free Newsletters!

Terms & Conditions and Privacy Policy.

Find a Doctor

Press Release Category

Press Release Archive

Stay Connected

  • Available on the Android Market
  • Available on the App Store