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The Relevance of CD44 and hyaluronan interaction in osteosarcoma progression and metastasis


Gvozdenovic, Ana. The Relevance of CD44 and hyaluronan interaction in osteosarcoma progression and metastasis. 2012, University of Zurich, Faculty of Science.

Abstract

Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS), the most common primary bone cancer in children and adolescents. Significant clinical improvements over the past several decades through the use of combination chemotherapy and surgery have led to a dramatic increase in the survival of patients with localized disease. However, patients with metastatic or recurrent disease continue to have a very poor prognosis, with <20% long term survival. The failure of treatment in these patients is often associated with gained resistance of tumor cells to chemotherapy. Therefore, it is of substantial relevance to identify molecular markers associated with the increased metastatic potential or chemoresistance, which may serve as diagnostic or prognostic factors. Acquiring insight into the basic biology of OS progression will make the identification of such new therapeutic targets possible with the final goal to develop treatment strategies that eradicate metastases and thereby improve the survival of OS patients. Metastasis is a complex multistep process which involves detachment of tumor cells from primary tumor mass, invasion of local stroma, intravasation, survival during transport in the circulation, arrest at distant organ sites, extravasation into corresponding parenchyma, adaptation to this new foreign tissue microenvironment and finally colonization in the distant organ. CD44 has been linked with increased metastatic spread in various types of cancer, however, its function in sarcomas has been only superficially addressed. CD44 and its numerous splice variants constitute a family of widely distributed type I transmembrane glycoproteins that serve as cell-cell and cell-matrix adhesion molecules and as principal receptors for hyaluronan (HA), a major component of the extracellular matrix in many tissues including bone. In this thesis, the prognostic value of CD44 expression for OS patients’ outcome and the biological relevance of CD44/HA interactions for in vitro malignant properties of OS tumor cells and for in vivo OS progression and metastasis in orthotopic xenograft OS mouse models were investigated. Our tissue microarray analysis of OS tumor specimens identified CD44 expression as an additional indicator of poor prognosis together with metastasis and resistance to chemotherapy, the two best established predictors of poor OS patient’s outcome. In vitro, CD44 expression correlated with the adhesion to HA and with cell migration. Moreover, cells with forced CD44 expression were more resistant to cisplatin. In vivo, our studies in different human xenograft OS mouse models revealed that CD44 gene products may play a dual role in regulating OS progression and metastases, depending on the cellular background. However, in the context of osteoblastic OS, the most common type of OS, our study demonstrated for the first time that CD44 promotes OS growth and dissemination in a HA-dependent manner and that CD44 expression is associated with in vitro enhanced migration rates and chemoresistance to cisplatin. This is also consistent with patient’s outcome as observed with tissue microarray analysis. On the other hand, in a subgroup of OS, where Ras signaling is increased, CD44 may act as a tumor suppressor probably by upregulation of merlin. Taken together, the findings presented in this thesis underscore the important role of CD44s/HA interaction in determining tumor malignancy in experimental OS. In conclusion, our results highlight CD44/HA interaction as a promising target for therapeutic intervention in this highly aggressive cancer type.

Abstract

Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS), the most common primary bone cancer in children and adolescents. Significant clinical improvements over the past several decades through the use of combination chemotherapy and surgery have led to a dramatic increase in the survival of patients with localized disease. However, patients with metastatic or recurrent disease continue to have a very poor prognosis, with <20% long term survival. The failure of treatment in these patients is often associated with gained resistance of tumor cells to chemotherapy. Therefore, it is of substantial relevance to identify molecular markers associated with the increased metastatic potential or chemoresistance, which may serve as diagnostic or prognostic factors. Acquiring insight into the basic biology of OS progression will make the identification of such new therapeutic targets possible with the final goal to develop treatment strategies that eradicate metastases and thereby improve the survival of OS patients. Metastasis is a complex multistep process which involves detachment of tumor cells from primary tumor mass, invasion of local stroma, intravasation, survival during transport in the circulation, arrest at distant organ sites, extravasation into corresponding parenchyma, adaptation to this new foreign tissue microenvironment and finally colonization in the distant organ. CD44 has been linked with increased metastatic spread in various types of cancer, however, its function in sarcomas has been only superficially addressed. CD44 and its numerous splice variants constitute a family of widely distributed type I transmembrane glycoproteins that serve as cell-cell and cell-matrix adhesion molecules and as principal receptors for hyaluronan (HA), a major component of the extracellular matrix in many tissues including bone. In this thesis, the prognostic value of CD44 expression for OS patients’ outcome and the biological relevance of CD44/HA interactions for in vitro malignant properties of OS tumor cells and for in vivo OS progression and metastasis in orthotopic xenograft OS mouse models were investigated. Our tissue microarray analysis of OS tumor specimens identified CD44 expression as an additional indicator of poor prognosis together with metastasis and resistance to chemotherapy, the two best established predictors of poor OS patient’s outcome. In vitro, CD44 expression correlated with the adhesion to HA and with cell migration. Moreover, cells with forced CD44 expression were more resistant to cisplatin. In vivo, our studies in different human xenograft OS mouse models revealed that CD44 gene products may play a dual role in regulating OS progression and metastases, depending on the cellular background. However, in the context of osteoblastic OS, the most common type of OS, our study demonstrated for the first time that CD44 promotes OS growth and dissemination in a HA-dependent manner and that CD44 expression is associated with in vitro enhanced migration rates and chemoresistance to cisplatin. This is also consistent with patient’s outcome as observed with tissue microarray analysis. On the other hand, in a subgroup of OS, where Ras signaling is increased, CD44 may act as a tumor suppressor probably by upregulation of merlin. Taken together, the findings presented in this thesis underscore the important role of CD44s/HA interaction in determining tumor malignancy in experimental OS. In conclusion, our results highlight CD44/HA interaction as a promising target for therapeutic intervention in this highly aggressive cancer type.

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Other titles:Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich
Item Type:Dissertation
Referees:Verrey François, Fuchs Bruno, Stamenkovic Ivan, Borsig Lubor
Communities & Collections:04 Faculty of Medicine > Balgrist University Hospital, Swiss Spinal Cord Injury Center
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2012
Deposited On:18 Jan 2013 10:48
Last Modified:14 Aug 2017 00:26
Number of Pages:122

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