Hyaluronan and the interaction between CD44 and epidermal growth factor receptor in oncogenic signaling and chemotherapy resistance in head and neck cancer
ABSTRACT To investigate whether hyaluronan (HA) and CD44 (hereinafter HA-CD44) promotes head and neck squamous cell carcinoma (HNSCC) chemotherapy resistance and whether HA-CD44 promotes epidermal growth factor receptor (EGFR)-mediated oncogenic signaling to alter chemotherapy sensitivity in HNSCC. Hyaluronan, a glycosaminoglycan component of the extracellular matrix, is a ligand for the transmembrane receptor CD44, which acts through multiple signaling pathways to influence cellular behavior. We recently determined that HA-CD44 promotes phospholipase C-mediated calcium signaling and cisplatin resistance in HNSCC.
Cell line study.
Tumor cell growth with various chemotherapeutic drugs (methotrexate, doxorubicin hydrochloride, adriamycin, and cisplatin) was measured in the presence or absence of HA and other inhibitors of the EGFR-mediated signaling pathway. Immunoblotting was used to study EGFR signaling. Migration assays provided one measure of tumor progression.
The addition of HA, but not HA plus anti-CD44 antibody, resulted in a 2-fold reduced ability of methotrexate and an 8-fold reduced ability of adriamycin to cause HNSCC cell death. Immunoblotting studies demonstrated that HA can promote an association between CD44 and EGFR as well as CD44-dependent activation of EGFR-mediated signaling. Migration assays demonstrated that HA-CD44 can promote tumor migration with EGFR signaling. The presence of AG1478, an EGFR inhibitor, and U0126, an extracellular signal-regulated kinase inhibitor, inhibited HA-mediated tumor growth, migration, and chemotherapy resistance.
Our results indicate that HA promotes CD44/EGFR interaction, EGFR-mediated oncogenic signaling, and chemotherapy resistance in HNSCC. Perturbation of HA-CD44-mediated signaling may be a promising and novel strategy to treat HNSCC.
- SourceAvailable from: Heiner Schäfer
[Show abstract] [Hide abstract]
- "produced by myofibroblasts  were found to stimulate drug resistance in drug-sensitive cancer cells, whereas disruption of endogenous hyaluronan-induced signalling suppresses cellular resistance to several drugs including doxorubicin, taxol, vincristine and methotrexate . Various reports demonstrate that hyaluronan and CD44 promote drug resistance in a variety of cancer cell types, including breast, lung, pancreas and head and neck carcinomas     . Accordingly, cleavage of hyaluronan by hyaluronidase treatment has been reported to enhance the action of various chemotherapeutic drugs . "
ABSTRACT: Tumors irrespective of their origin are heterogenous cellular entities whose growth and progression greatly depend on reciprocal interactions between genetically altered (neoplastic) cells and their non-neoplastic microenvironment. Thus, microenvironmental factors promote many steps in carcinogenesis, e.g. proliferation, invasion, angiogenesis, metastasis and chemoresistance. Drug resistance, either intrinsic or acquired, essentially limits the efficacy of chemotherapy in many cancer patients. To some extent, this resistance is maintained by reduced drug accumulation, alterations in drug targets and increased repair of drug-induced DNA damage. However, the pivotal mechanism by which tumor cells elude the cytotoxic effect of chemotherapeutic drugs is their efficient protection from induction and excecution of apoptosis. It is meanwhile well established that cellular and non-cellular components of the tumoral microenvironment, e.g. myofibroblasts and extracellular matrix (ECM) proteins, respectively, contribute to the anti-apoptotic protection of tumor cells. Cellular adhesion molecules (e.g. L1CAM or CD44), chemokines (e.g. CXCL12), integrins and other ECM receptors which are involved in direct and indirect interactions between tumor cells and their microenvironment have been identified as suitable molecular targets to overcome chemoresistance. Accordingly, several therapeutic strategies based on these targets have been already elaborated and tested in preclinical and clinical studies, including inhibitors and blocking antibodies for CD44/hyaluronan, integrins, L1CAM and CXCL12. Even though these approaches turned out to be promising, the upcoming challenge will be to prove the efficacy of these strategies in improving treatment and prognosis of cancer patients.Current pharmaceutical biotechnology 05/2011; 13(11):2259-72. DOI:10.2174/138920112802501999 · 2.51 Impact Factor
[Show abstract] [Hide abstract]
- "In patients with interstitial cystitis it has been reported that oral or intravesical administration of HA reduced bladder inflammation and 'replenized' the GAG layer (Theoharides et al., 2008), and that intravesical administration of HA is regarded as a safe and efficacious method of treatment of patients with interstitial cystitis/ painful bladder syndrome (Porru et al., 2008). Interactions of HA with CD44 induce activation of receptor tyrosine kinases and promote 'bitter' effects, such as drug resistance in a variety of cancer cell types, including breast, lung and head and neck carcinomas, and lymphoma (Misra et al., 2005; Wang and Bourguignon, 2006; Cordo Russo et al., 2008). An anticipated 'sweet' effect of small HA oligomers, acting as antagonists to high-molecular-weight HA–CD44 interactions, may be proved to be useful in therapeutic strategies aimed at preventing tumour recurrence from therapyresistant sub-populations within malignant cancers (Toole and Slomiany, 2008). "
ABSTRACT: The extracellular matrix (ECM) plays a significant role in the structure and function of the lung. The ECM is a three-dimensional fibre mesh, comprised of various interconnected and intercalated macromolecules, among which are the glycosaminoglycans (GAG). GAG are long, linear and highly charged, heterogeneous polysaccharides that are composed of a variable number of repeating disaccharide units (macromolecular sugars) and most of them, as their name implies, have a sweet taste. In the lung, GAG support the structure of the interstitium, the subepithelial tissue and the bronchial walls, and are secreted in the airway secretions. Besides maintaining lung tissue structure, GAG also play an important role in lung function as they regulate hydration and water homeostasis, modulate the inflammatory response and influence lung tissue repair and remodelling. However, depending on their size and/or degree of sulphation, and their immobilization or solubilization in the ECM, specific GAG in the lung either live up to their sweet taste/name, supporting normal lung physiology, or they are associated to 'bitter' effects, related to lung pathology. The present review discusses the biological role of GAG in the lung as well as the involvement of these molecules in various respiratory diseases. Given the great structural diversity of GAG, understanding the changes in GAG expression that occur in lung diseases may lead to novel targets for pharmacological intervention in order to prevent and/or to treat a range of lung diseases.British Journal of Pharmacology 07/2009; 157(7):1111-27. DOI:10.1111/j.1476-5381.2009.00279.x · 4.99 Impact Factor
- "As yet, it is unclear how expression of molecules such as CD44 and CD133 is related to the maintenance of malignant stem cell function. CD44 was initially characterized as a cell adhesion molecule binding primarily to hyaluronan but has since been shown to have signalling functions through interactions with several types of cell surface receptors (Turley et al. 2002; Wang & Bourguignon, 2006). The functions of CD133 are also unclear, but Prominin1, its murine homologue, has been associated with control of the symmetry of stem cell division in neural tissues (Kania et al. 2005). "
Article: Epithelial stem cells and malignancy[Show abstract] [Hide abstract]
ABSTRACT: The renewal of normal epithelia depends on a small sub-population of cells, termed somatic stem cells, whose primary characteristic is an ability for indefinite self-renewal. Evidence is accumulating that the growth of tumours similarly depends on a sub-population of malignant stem cells, often termed tumour-initiating cells. Tumour-initiating sub-populations within solid tumours have been identified by their cell surface expression of various phenotypic markers and by their ability to regenerate tumours in immune-deficient mice. Cells with such clonogenic abilities differ consistently from the remainder of the cell population in cellular properties such as size, adhesiveness, dye exclusion, and patterns of gene expression. Sub-populations of malignant cells freshly isolated from tumours also show differing patterns of expression of molecules related to stem cell maintenance and asymmetric division. As the cells ultimately responsible for tumour renewal, malignant stem cells appear to form the necessary target of therapy but some findings indicate greater resistance of these cells to the induction of apoptotic cell death and their potential failure to respond effectively to standard therapeutic procedures. Of particular interest, cells with clonogenic properties and expression patterns similar to those of tumour-initiating cells in vivo persist in malignant cell lines and show similar apoptotic resistance. Cell lines may thus provide a model for analysis of malignant stem cell properties and may be useful for the development of appropriate methods for their elimination.Journal of Anatomy 07/2008; 213(1):45-51. DOI:10.1111/j.1469-7580.2008.00895.x · 2.23 Impact Factor