Related Experiment Video
Updated: Mar 23, 2026
Induction and Analysis of Epithelial to Mesenchymal Transition
Published on: August 27, 2013
Myofibroblasts have an impact on expression, dimerization and signaling of different ErbB receptors in OSCC cells
Robert Büttner1,2, Alexander Berndt3, Christina Valkova2
1a Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena , Jena , Germany.
Introduction:
Receptors of the ErbB family belong to the key players in cancer development and are targets of several therapeutic approaches. Their functional dependency on the tumor microenvironment, especially on CAFs is albeit still poorly understood. Our objective was to investigate the impact of CAF secretome on ErbB receptor expression and signaling behavior in OSCC.
Methods:
Stimulation of PE/CA-PJ15 OSCC cells with conditioned media of TGF-β1-activated fibroblasts was used as model system for CAF to cancer cell communication. Thereby costimulation with inhibitors against matrix metalloproteinases (MMPs), epidermal growth factor receptor (EGFR), MAPK/ERK kinase (MEK), phosphoinositide-3 kinase (PI3-K), signal transducer and activator of transcription 3 (Stat3) or knockdown of Her3 by siRNA was utilized for detailed investigation of the expression, dimerization and signaling pattern of ErbB in western blot and coimmunoprecipitation.
Results:
Our results show that soluble factors in activated fibroblast secretome stimulate metalloproteinase activity in the membrane of cancer cells. Thereby ligands are released that activate EGFR and subsequently upregulates EGFR expression via the STAT3 pathway. Simultaneously, the expression of PKCɛ was enhanced via a PI3-kinase/Akt-mediated pathway and a negative feedback regulation loop on EGFR downstream signaling generated. Furthermore, the activated fibroblasts secretome stimulated the highly oncogenic hetero-dimerization between HER3 and p95HER2. That protein association is inversely dependent on the expression level of HER3.
Conclusions:
Our results demonstrate that the activated fibroblasts secretome can induce a counterbalanced regulation of protein expression, downstream signaling and the dimerization patterns of different ErbB receptor subtypes in the cancer cell. Thus, the combinatorial targeting of CAFs and selective ErbB receptor subtype inhibitors may provide a useful approach in cancer therapy.
Insights
Cancer-associated fibroblast (CAF) secretomes influence ErbB receptor signaling in oral squamous cell carcinoma (OSCC). Targeting CAFs and ErbB receptors may improve cancer therapy.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Signaling
Background:
- ErbB receptors are crucial in cancer development and therapeutic targets.
- The role of cancer-associated fibroblasts (CAFs) in ErbB receptor function is poorly understood.
- Investigating CAF secretome impact on ErbB signaling in oral squamous cell carcinoma (OSCC) is essential.
Purpose of the Study:
- To elucidate the effect of CAF secretome on ErbB receptor expression and signaling in OSCC.
- To understand the molecular mechanisms linking CAFs and ErbB receptor activity.
- To identify potential therapeutic strategies targeting CAF-cancer cell interactions.
Main Methods:
- Utilized OSCC cells stimulated with conditioned media from TGF-β1-activated fibroblasts (model for CAF-cancer cell communication).
- Employed inhibitors for matrix metalloproteinases (MMPs), EGFR, MEK, PI3-K, and STAT3, alongside Her3 siRNA.
- Analyzed ErbB expression, dimerization, and signaling patterns using western blot and coimmunoprecipitation.
Main Results:
- CAF secretome activated cancer cell membrane metalloproteinases, releasing ligands that activated EGFR.
- EGFR expression was upregulated via the STAT3 pathway; PKCɛ expression was enhanced via PI3-kinase/Akt.
- CAF secretome promoted HER3/p95HER2 heterodimerization, inversely dependent on HER3 expression.
Conclusions:
- Activated CAF secretome orchestrates a balanced regulation of ErbB receptor expression, signaling, and dimerization in cancer cells.
- Combinatorial targeting of CAFs and selective ErbB receptor inhibitors shows therapeutic promise for OSCC.
- Understanding these interactions can lead to novel, more effective cancer treatment strategies.
Related Concept Videos
02:38Mitogens and the Cell Cycle
01:17Intracellular Signaling Affects Focal Adhesions
Some...
02:23Abnormal Proliferation
01:16Cell Motility through Blebbing
Blebbing Through the Matrix
In multicellular...
01:16TGF - β Signaling Pathway
01:22Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal