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PDF (Thesis.Pdf) THE EFFECTS OF BEHAVIORAL STRESS AND ENDOTHELIN RECEPTOR ANTAGONISTS ON CANCER Thesis by Jennifer Pielstick Montgomery In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 2007 (Defended May 15, 2007) ii © 2007 Jennifer Pielstick Montgomery All Rights Reserved iii ACKNOWLEDGEMENTS I would like to extend my gratitude toward all the people who have contributed to my development personally and professionally during my graduate studies at Caltech. This work would not have been possible without the support of my advisor, Paul H. Patterson. He allowed me the freedom to design my own experiments and work independently. I would also like to thank my committee members, Kai Zinn, Ellen Rothenberg and Scott Fraser, for their time and constructive comments. Our discussions always provided new insights into my experiments. I also thank Patterson Lab members past and present, especially Bradley Kerr, Kristina Holmberg, Jan Ko, Limin Shi, Benjamin Deverman and Wally Bugg, for their advice and their friendship. I would like to show my appreciation to Doreen McDowell and Bill Lease for their support and long conversations. Thanks to Liz Ayala and Kathleen Hamilton for their administrative help. Additionally, I am very grateful to Shelley Diamond for her technical expertise and discussions, both professional and personal. I would like to dedicate this work to my family. To my parents, Kristi and John, you have always supported me and allowed me to pursue my dreams. You have contributed substantially to my success. To my siblings, Martha and Robert, you always made coming home fun even as I watched you finish your degrees while I continued to work on my own. To my husband, Fraser, there are not sufficient words to thank you for your daily encouragement and love. You have supported me through the ups and downs of graduate school and I treasure every day with you. To my son, Ewan, you are truly amazing and you make each day precious with a single smile. iv ABSTRACT This work examines two potential mediators of cancer. Section one considers the putative link between behavioral stress and cancer. We developed a stress paradigm of alternating established stressors that dramatically increases serum corticosterone and causes thymus involution. When this stress paradigm was applied to mice implanted with either melanoma or lymphosarcoma tumors we observed no alteration in the growth of either tumor. In addition, we applied a protocol established in another laboratory that demonstrated a dramatic enhancement of lymphosarcoma tumors following rotational stress (Riley V. (1981). Psychoneuroendocrine influences on immunocompetence and neoplasia. Science 212, 1100-1109). We find no significant effect on lymphosarcoma progression. Therefore, under the conditions used in our studies, strong behavioral stress does not influence tumor growth. Section two considers the effects of endothelin receptor (ETR) antagonists on cancer progression. Their ability to inhibit growth of many cancers is well documented, but similar research on glioma has been limited. We find that two ETRB-specific antagonists, BQ788 and A-192621, reduce the number of viable cells in glioma and melanoma cell lines in a dose- and time-dependent manner. In glioma cells, A-192621 induces a G2/M arrest, decreases the mean number of cell divisions and enhances apoptosis. BQ123, an ETRA-specific antagonist, has no effect on cell viability. A- 192621 also up-regulates several DNA damage-inducible genes. Interestingly, reducing ETRB expression with small interfering RNAs does not abrogate the effects of either A- 192621 or BQ788 in glioma or melanoma cells. Thus, while ETRB antagonists are effective against glioma, it appears unlikely that their therapeutic effects are mediated by v ETRB. Further investigation is needed to define the mechanism by which these compounds decrease cell viability. vi TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................................................................................iii ABSTRACT...................................................................................................................... iv TABLE OF CONTENTS ................................................................................................ vi SECTION I........................................................................................................................ 1 CHAPTER I: EVIDENCE FOR AN ASSOCIATION BETWEEN STRESS AND CANCER ............... 2 Stress........................................................................................................................... 3 Stress and the immune system..................................................................................... 4 Animal studies of stress and cancer............................................................................ 8 Stress and cancer in the clinic .................................................................................. 14 References................................................................................................................. 17 CHAPTER II: BEHAVIORAL STRESS AND TUMOR PROGRESSION ..................................... 32 Abstract..................................................................................................................... 33 Introduction............................................................................................................... 33 Materials and Methods ............................................................................................. 33 Results....................................................................................................................... 34 Figure 1..................................................................................................................... 34 Figure 2..................................................................................................................... 35 Figure 3..................................................................................................................... 35 Discussion................................................................................................................. 35 Acknowledgements.................................................................................................... 36 References................................................................................................................. 36 vii CHAPTER III: CONCLUDING REMARKS........................................................................... 37 SECTION II .................................................................................................................... 42 CHAPTER I: EVIDENCE FOR AN ASSOCIATION BETWEEN THE ENDOTHELIN AXIS AND CANCER ......................................................................................................................... 43 The endothelin system............................................................................................... 44 Endothelins and development ................................................................................... 46 Endothelins and cancer............................................................................................. 47 Endothelin receptor antagonists............................................................................... 51 Endothelins and melanoma....................................................................................... 52 Endothelins and glioma ............................................................................................ 57 Table 1 ...................................................................................................................... 62 Table 2 ...................................................................................................................... 64 References................................................................................................................. 66 CHAPTER II: ENDOTHELIN RECEPTOR B ANTAGONISTS DECREASE GLIOMA VIABILITY INDEPENDENTLY OF THEIR COGNATE RECEPTOR......................................................... 100 Abstract................................................................................................................... 101 Introduction............................................................................................................. 101 Materials and Methods ........................................................................................... 103 Results..................................................................................................................... 106 Discussion............................................................................................................... 111 Acknowledgements.................................................................................................. 112 References............................................................................................................... 114 Tables...................................................................................................................... 121 viii Figure Legends ....................................................................................................... 122 Figure 1................................................................................................................... 124 Figure 2..................................................................................................................
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