Dietmar W. Siemann is the editor of Tumor Microenvironment, published by Wiley.

"Overall, it would be useful to basic scientists interested in understanding the role of stroma, in particular the role of hypoxia, in cancer progression." (Doody's, 16 September 2011) "Tumor Microenvironment is informative and current. This field of study is already evolving beyond the microenvironment into the host systemic environment and the role of endocrine factors in tumor progression. If a second edition of the book is published, it will most certainly encompass these newly emerging concepts." (Elsevier, 2011)

• Preface xiiiList of Contributors xv1 The Microenvironment in Cancer 1Nicole N. Parker and Dietmar W. Siemann1.1 Introduction 11.2 A highly selective process is required to obtain the cancer phenotype 11.3 The cancer phenotype 21.4 The extracellular matrix 31.5 Motility, invasion, and metastatic ability 41.6 Impact of the tumor microenvironment on the control of cancer 41.7 Targeting the tumor microenvironment 51.8 Summary 5References 62 Establishing the Tumor Microenvironment 7Allison S. Betof and Mark W. Dewhirst2.1 Introduction 72.2 From cancerous cells to a tumor 82.3 A tumor is more than cancer cells and fibroblasts 92.4 Communication between the tumor cells and stroma 112.5 Hypoxia and angiogenesis 122.6 Conclusion 24Acknowledgements 24References 24Further reading 333 Contributions of the Extracellular Matrix to Tumorigenesis 35Marie Schluterman Burdine and Rolf A. Brekken3.1 The extracellular matrix 353.2 Manipulation of the ECM during tumor development 383.3 Matricellular proteins and their complex effects on tumor development 393.4 Conclusion 47References 484 Matrix Metalloproteinases and Their Inhibitors – Friend or Foe 53Mumtaz V. Rojiani, Marzenna Wiranowska and Amyn M. Rojiani4.1 Introduction 534.2 Matrix metalloproteinases 544.3 Tissue inhibitors of matrix metalloproteinases 634.4 Concluding comments 69References 695 Role of Tumor-Associated Macrophages (TAM) in Cancer Related Inflammation 77Antonio Sica and Chiara Porta5.1 Introduction 775.2 Functional plasticity of macrophages 775.3 Macrophages as key orchestrators of cancer-related inflammation 795.4 Recruitment and differentiation of TAM 815.5 Protumoral functions of TAM 835.6 Molecular determinants of TAM functions 875.7 Therapeutic targeting of TAM 895.8 Conclusions 91References 926 Bone Marrow Stroma and the Leukemic Microenvironment 99William B. Slayton and Zhongbo Hu6.1 Introduction 996.2 Components and function of the normal bone marrow microenvironment 996.3 Leukemia and its microenvironment 1196.4 Summary 123References 1247 Microenvironment Factors Influencing Skeletal Metastases 135Alessandro Fatatis, Julia A. D’Ambrosio, Whitney L. Jamieson, Danielle L. Jernigan and Mike R. Russell7.1 Introduction 1357.2 The bone microenvironment as a target for cancer cell dissemination 1367.3 Roles of the bone microenvironment in promoting the arrest of circulating cancer cells at the skeleton 1377.4 Concluding remarks 153References 1538 Premetastatic Niches 161Kevin L. Bennewith, Janine T. Erler and Amato J. Giaccia8.1 Introduction 1618.2 ‘Seeds’ influencing the ‘Soil’ 1628.3 Cellular components of premetastatic niches 1648.4 ECM components of premetastatic niches 1668.5 Premetastatic niche formation precedes metastatic growth 1708.6 Therapeutic targeting of the premetastatic niche 1728.7 Evidence for premetastatic niches in the clinic 1748.8 Concluding remarks 174References 1759 Hypoxia, Anerobic Metabolism, and Interstitial Hypertension 183Michael F. Milosevic9.1 Introduction 1839.2 Pathophysiology of the tumor microenvironment 1849.3 Evaluating the tumor microenvironment 1899.4 Biologic and therapeutic implications 1959.5 Clinical implications 1999.6 Summary 201References 20110 Hypoxia and the DNA Damage Response 207Isabel M. Pires, Rachel Poole and Ester M. Hammond10.1 Introduction 20710.2 The DNA damage response 20810.3 Hypoxia regulation of DNA repair 21510.4 Context synthetic lethality: exploiting hypoxic deregulation of DNA repair 22010.5 Conclusions 221References 22111 Non-Invasive Imaging of the Tumor Microenvironment 229Bénédicte F. Jordan and Bernard Gallez11.1 Introduction 22911.2 Imaging tumor vasculature, perfusion, and angiogenesis 22911.3 Imaging tumor hypoxia: chronic and acute 23411.4 Imaging tumor oxygen consumption 24011.5 EPR oximetry 24011.6 Imaging tumor interstitial fluid pressure (IFP) 24411.7 Imaging tumor pH 24511.8 Imaging tumor redox status 24811.9 Imaging tumor response 25011.10 Optimizing therapeutic intervention using molecular imaging 25611.11 Conclusions 261References 261Further reading 27012 Hypoxia-Inducible Factor 1 (HIF1) Mediated Adaptive Responses in the Solid Tumor 271Tereza Goliasova and Nicholas C. Denko12.1 Introduction 27112.2 Molecular consequences of tumor hypoxia 27212.3 Hypoxia inducible factor 1 27312.4 HIF-1 subunits and domain structure 27312.5 Regulation of HIF-1α protein stability and activity by post-translational modifications 27412.6 HIF isoforms 27512.7 Oxygen-independent HIF signaling 27612.8 HIF target genes 27712.9 Hypoxia and oxygen delivery 27912.10 Hypoxia and glucose metabolism 28012.11 Hypoxia and acidosis 28112.12 Hypoxia and metastasis 28212.13 Therapeutic implications 283References 28513 Regulation of the Unfolded Protein Response in Cancer 291Jing Zhang and Albert C. Koong13.1 Introduction 29113.2 The UPR signaling cascade 29213.3 Hypoxia activates UPR 29513.4 UPR and expression of UPR-targeted genes in cancer 29813.5 Concluding remarks 304References 30414 Influence of Hypoxia on Metastatic Spread 311Richard P. Hill and Naz Chaudary14.1 Introduction 31114.2 The metastatic process 31314.3 The tumor microenvironment and metastasis 31614.4 Summary 326References 32615 Drug Penetration and Therapeutic Resistance 329Andrew I. Minchinton and Alastair H. Kyle15.1 Introduction 32915.2 Tumor microenvironment 33015.3 Drug penetration 33415.4 In vitro tumor models 33815.5 Conclusions 346References 34716 Impact on Radiotherapy 353Michael R. Horsman, Jens Overgaard and Dietmar W. Siemann16.1 Introduction 35316.2 The tumour vasculature and microenvironment 35316.3 Influence of tumor hypoxia on radiation therapy 35616.4 Reducing hypoxia by increasing oxygen delivery 35816.5 Radiosensitizing hypoxic cells 36316.6 Killing the resistant cell population 36516.7 Vascular targeting approaches 36616.8 Conclusions and future perspectives 367References 36817 HIF-1 Inhibitors for Cancer Therapy 377Annamaria Rapisarda and Giovanni Melillo17.1 Introduction 37717.2 Small molecule inhibitors of HIF- 1 37817.3 Exploiting HIF-1 inhibitors in combination strategies 39117.4 Conclusions 392Acknowledgements 392References 39318 Vascular-Targeted Molecular Therapy 401Graeme J. Dougherty and Shona T. Dougherty18.1 Introduction 40118.2 Approaches to targeting tumor vasculature in vivo 40318.3 Alternative targeting strategies 41218.4 Concluding remarks 413Acknowledgements 413References 413Index 421

Dietmar W. Siemann is the editor of Tumor Microenvironment, published by Wiley.

"Overall, it would be useful to basic scientists interested in understanding the role of stroma, in particular the role of hypoxia, in cancer progression." (Doody's, 16 September 2011) "Tumor Microenvironment is informative and current. This field of study is already evolving beyond the microenvironment into the host systemic environment and the role of endocrine factors in tumor progression. If a second edition of the book is published, it will most certainly encompass these newly emerging concepts." (Elsevier, 2011)

• Preface xiiiList of Contributors xv1 The Microenvironment in Cancer 1Nicole N. Parker and Dietmar W. Siemann1.1 Introduction 11.2 A highly selective process is required to obtain the cancer phenotype 11.3 The cancer phenotype 21.4 The extracellular matrix 31.5 Motility, invasion, and metastatic ability 41.6 Impact of the tumor microenvironment on the control of cancer 41.7 Targeting the tumor microenvironment 51.8 Summary 5References 62 Establishing the Tumor Microenvironment 7Allison S. Betof and Mark W. Dewhirst2.1 Introduction 72.2 From cancerous cells to a tumor 82.3 A tumor is more than cancer cells and fibroblasts 92.4 Communication between the tumor cells and stroma 112.5 Hypoxia and angiogenesis 122.6 Conclusion 24Acknowledgements 24References 24Further reading 333 Contributions of the Extracellular Matrix to Tumorigenesis 35Marie Schluterman Burdine and Rolf A. Brekken3.1 The extracellular matrix 353.2 Manipulation of the ECM during tumor development 383.3 Matricellular proteins and their complex effects on tumor development 393.4 Conclusion 47References 484 Matrix Metalloproteinases and Their Inhibitors – Friend or Foe 53Mumtaz V. Rojiani, Marzenna Wiranowska and Amyn M. Rojiani4.1 Introduction 534.2 Matrix metalloproteinases 544.3 Tissue inhibitors of matrix metalloproteinases 634.4 Concluding comments 69References 695 Role of Tumor-Associated Macrophages (TAM) in Cancer Related Inflammation 77Antonio Sica and Chiara Porta5.1 Introduction 775.2 Functional plasticity of macrophages 775.3 Macrophages as key orchestrators of cancer-related inflammation 795.4 Recruitment and differentiation of TAM 815.5 Protumoral functions of TAM 835.6 Molecular determinants of TAM functions 875.7 Therapeutic targeting of TAM 895.8 Conclusions 91References 926 Bone Marrow Stroma and the Leukemic Microenvironment 99William B. Slayton and Zhongbo Hu6.1 Introduction 996.2 Components and function of the normal bone marrow microenvironment 996.3 Leukemia and its microenvironment 1196.4 Summary 123References 1247 Microenvironment Factors Influencing Skeletal Metastases 135Alessandro Fatatis, Julia A. D’Ambrosio, Whitney L. Jamieson, Danielle L. Jernigan and Mike R. Russell7.1 Introduction 1357.2 The bone microenvironment as a target for cancer cell dissemination 1367.3 Roles of the bone microenvironment in promoting the arrest of circulating cancer cells at the skeleton 1377.4 Concluding remarks 153References 1538 Premetastatic Niches 161Kevin L. Bennewith, Janine T. Erler and Amato J. Giaccia8.1 Introduction 1618.2 ‘Seeds’ influencing the ‘Soil’ 1628.3 Cellular components of premetastatic niches 1648.4 ECM components of premetastatic niches 1668.5 Premetastatic niche formation precedes metastatic growth 1708.6 Therapeutic targeting of the premetastatic niche 1728.7 Evidence for premetastatic niches in the clinic 1748.8 Concluding remarks 174References 1759 Hypoxia, Anerobic Metabolism, and Interstitial Hypertension 183Michael F. Milosevic9.1 Introduction 1839.2 Pathophysiology of the tumor microenvironment 1849.3 Evaluating the tumor microenvironment 1899.4 Biologic and therapeutic implications 1959.5 Clinical implications 1999.6 Summary 201References 20110 Hypoxia and the DNA Damage Response 207Isabel M. Pires, Rachel Poole and Ester M. Hammond10.1 Introduction 20710.2 The DNA damage response 20810.3 Hypoxia regulation of DNA repair 21510.4 Context synthetic lethality: exploiting hypoxic deregulation of DNA repair 22010.5 Conclusions 221References 22111 Non-Invasive Imaging of the Tumor Microenvironment 229Bénédicte F. Jordan and Bernard Gallez11.1 Introduction 22911.2 Imaging tumor vasculature, perfusion, and angiogenesis 22911.3 Imaging tumor hypoxia: chronic and acute 23411.4 Imaging tumor oxygen consumption 24011.5 EPR oximetry 24011.6 Imaging tumor interstitial fluid pressure (IFP) 24411.7 Imaging tumor pH 24511.8 Imaging tumor redox status 24811.9 Imaging tumor response 25011.10 Optimizing therapeutic intervention using molecular imaging 25611.11 Conclusions 261References 261Further reading 27012 Hypoxia-Inducible Factor 1 (HIF1) Mediated Adaptive Responses in the Solid Tumor 271Tereza Goliasova and Nicholas C. Denko12.1 Introduction 27112.2 Molecular consequences of tumor hypoxia 27212.3 Hypoxia inducible factor 1 27312.4 HIF-1 subunits and domain structure 27312.5 Regulation of HIF-1α protein stability and activity by post-translational modifications 27412.6 HIF isoforms 27512.7 Oxygen-independent HIF signaling 27612.8 HIF target genes 27712.9 Hypoxia and oxygen delivery 27912.10 Hypoxia and glucose metabolism 28012.11 Hypoxia and acidosis 28112.12 Hypoxia and metastasis 28212.13 Therapeutic implications 283References 28513 Regulation of the Unfolded Protein Response in Cancer 291Jing Zhang and Albert C. Koong13.1 Introduction 29113.2 The UPR signaling cascade 29213.3 Hypoxia activates UPR 29513.4 UPR and expression of UPR-targeted genes in cancer 29813.5 Concluding remarks 304References 30414 Influence of Hypoxia on Metastatic Spread 311Richard P. Hill and Naz Chaudary14.1 Introduction 31114.2 The metastatic process 31314.3 The tumor microenvironment and metastasis 31614.4 Summary 326References 32615 Drug Penetration and Therapeutic Resistance 329Andrew I. Minchinton and Alastair H. Kyle15.1 Introduction 32915.2 Tumor microenvironment 33015.3 Drug penetration 33415.4 In vitro tumor models 33815.5 Conclusions 346References 34716 Impact on Radiotherapy 353Michael R. Horsman, Jens Overgaard and Dietmar W. Siemann16.1 Introduction 35316.2 The tumour vasculature and microenvironment 35316.3 Influence of tumor hypoxia on radiation therapy 35616.4 Reducing hypoxia by increasing oxygen delivery 35816.5 Radiosensitizing hypoxic cells 36316.6 Killing the resistant cell population 36516.7 Vascular targeting approaches 36616.8 Conclusions and future perspectives 367References 36817 HIF-1 Inhibitors for Cancer Therapy 377Annamaria Rapisarda and Giovanni Melillo17.1 Introduction 37717.2 Small molecule inhibitors of HIF- 1 37817.3 Exploiting HIF-1 inhibitors in combination strategies 39117.4 Conclusions 392Acknowledgements 392References 39318 Vascular-Targeted Molecular Therapy 401Graeme J. Dougherty and Shona T. Dougherty18.1 Introduction 40118.2 Approaches to targeting tumor vasculature in vivo 40318.3 Alternative targeting strategies 41218.4 Concluding remarks 413Acknowledgements 413References 413Index 421

Dietmar W. Siemann is the editor of Tumor Microenvironment, published by Wiley.

"Overall, it would be useful to basic scientists interested in understanding the role of stroma, in particular the role of hypoxia, in cancer progression." (Doody's, 16 September 2011) "Tumor Microenvironment is informative and current. This field of study is already evolving beyond the microenvironment into the host systemic environment and the role of endocrine factors in tumor progression. If a second edition of the book is published, it will most certainly encompass these newly emerging concepts." (Elsevier, 2011)

• Preface xiiiList of Contributors xv1 The Microenvironment in Cancer 1Nicole N. Parker and Dietmar W. Siemann1.1 Introduction 11.2 A highly selective process is required to obtain the cancer phenotype 11.3 The cancer phenotype 21.4 The extracellular matrix 31.5 Motility, invasion, and metastatic ability 41.6 Impact of the tumor microenvironment on the control of cancer 41.7 Targeting the tumor microenvironment 51.8 Summary 5References 62 Establishing the Tumor Microenvironment 7Allison S. Betof and Mark W. Dewhirst2.1 Introduction 72.2 From cancerous cells to a tumor 82.3 A tumor is more than cancer cells and fibroblasts 92.4 Communication between the tumor cells and stroma 112.5 Hypoxia and angiogenesis 122.6 Conclusion 24Acknowledgements 24References 24Further reading 333 Contributions of the Extracellular Matrix to Tumorigenesis 35Marie Schluterman Burdine and Rolf A. Brekken3.1 The extracellular matrix 353.2 Manipulation of the ECM during tumor development 383.3 Matricellular proteins and their complex effects on tumor development 393.4 Conclusion 47References 484 Matrix Metalloproteinases and Their Inhibitors – Friend or Foe 53Mumtaz V. Rojiani, Marzenna Wiranowska and Amyn M. Rojiani4.1 Introduction 534.2 Matrix metalloproteinases 544.3 Tissue inhibitors of matrix metalloproteinases 634.4 Concluding comments 69References 695 Role of Tumor-Associated Macrophages (TAM) in Cancer Related Inflammation 77Antonio Sica and Chiara Porta5.1 Introduction 775.2 Functional plasticity of macrophages 775.3 Macrophages as key orchestrators of cancer-related inflammation 795.4 Recruitment and differentiation of TAM 815.5 Protumoral functions of TAM 835.6 Molecular determinants of TAM functions 875.7 Therapeutic targeting of TAM 895.8 Conclusions 91References 926 Bone Marrow Stroma and the Leukemic Microenvironment 99William B. Slayton and Zhongbo Hu6.1 Introduction 996.2 Components and function of the normal bone marrow microenvironment 996.3 Leukemia and its microenvironment 1196.4 Summary 123References 1247 Microenvironment Factors Influencing Skeletal Metastases 135Alessandro Fatatis, Julia A. D’Ambrosio, Whitney L. Jamieson, Danielle L. Jernigan and Mike R. Russell7.1 Introduction 1357.2 The bone microenvironment as a target for cancer cell dissemination 1367.3 Roles of the bone microenvironment in promoting the arrest of circulating cancer cells at the skeleton 1377.4 Concluding remarks 153References 1538 Premetastatic Niches 161Kevin L. Bennewith, Janine T. Erler and Amato J. Giaccia8.1 Introduction 1618.2 ‘Seeds’ influencing the ‘Soil’ 1628.3 Cellular components of premetastatic niches 1648.4 ECM components of premetastatic niches 1668.5 Premetastatic niche formation precedes metastatic growth 1708.6 Therapeutic targeting of the premetastatic niche 1728.7 Evidence for premetastatic niches in the clinic 1748.8 Concluding remarks 174References 1759 Hypoxia, Anerobic Metabolism, and Interstitial Hypertension 183Michael F. Milosevic9.1 Introduction 1839.2 Pathophysiology of the tumor microenvironment 1849.3 Evaluating the tumor microenvironment 1899.4 Biologic and therapeutic implications 1959.5 Clinical implications 1999.6 Summary 201References 20110 Hypoxia and the DNA Damage Response 207Isabel M. Pires, Rachel Poole and Ester M. Hammond10.1 Introduction 20710.2 The DNA damage response 20810.3 Hypoxia regulation of DNA repair 21510.4 Context synthetic lethality: exploiting hypoxic deregulation of DNA repair 22010.5 Conclusions 221References 22111 Non-Invasive Imaging of the Tumor Microenvironment 229Bénédicte F. Jordan and Bernard Gallez11.1 Introduction 22911.2 Imaging tumor vasculature, perfusion, and angiogenesis 22911.3 Imaging tumor hypoxia: chronic and acute 23411.4 Imaging tumor oxygen consumption 24011.5 EPR oximetry 24011.6 Imaging tumor interstitial fluid pressure (IFP) 24411.7 Imaging tumor pH 24511.8 Imaging tumor redox status 24811.9 Imaging tumor response 25011.10 Optimizing therapeutic intervention using molecular imaging 25611.11 Conclusions 261References 261Further reading 27012 Hypoxia-Inducible Factor 1 (HIF1) Mediated Adaptive Responses in the Solid Tumor 271Tereza Goliasova and Nicholas C. Denko12.1 Introduction 27112.2 Molecular consequences of tumor hypoxia 27212.3 Hypoxia inducible factor 1 27312.4 HIF-1 subunits and domain structure 27312.5 Regulation of HIF-1α protein stability and activity by post-translational modifications 27412.6 HIF isoforms 27512.7 Oxygen-independent HIF signaling 27612.8 HIF target genes 27712.9 Hypoxia and oxygen delivery 27912.10 Hypoxia and glucose metabolism 28012.11 Hypoxia and acidosis 28112.12 Hypoxia and metastasis 28212.13 Therapeutic implications 283References 28513 Regulation of the Unfolded Protein Response in Cancer 291Jing Zhang and Albert C. Koong13.1 Introduction 29113.2 The UPR signaling cascade 29213.3 Hypoxia activates UPR 29513.4 UPR and expression of UPR-targeted genes in cancer 29813.5 Concluding remarks 304References 30414 Influence of Hypoxia on Metastatic Spread 311Richard P. Hill and Naz Chaudary14.1 Introduction 31114.2 The metastatic process 31314.3 The tumor microenvironment and metastasis 31614.4 Summary 326References 32615 Drug Penetration and Therapeutic Resistance 329Andrew I. Minchinton and Alastair H. Kyle15.1 Introduction 32915.2 Tumor microenvironment 33015.3 Drug penetration 33415.4 In vitro tumor models 33815.5 Conclusions 346References 34716 Impact on Radiotherapy 353Michael R. Horsman, Jens Overgaard and Dietmar W. Siemann16.1 Introduction 35316.2 The tumour vasculature and microenvironment 35316.3 Influence of tumor hypoxia on radiation therapy 35616.4 Reducing hypoxia by increasing oxygen delivery 35816.5 Radiosensitizing hypoxic cells 36316.6 Killing the resistant cell population 36516.7 Vascular targeting approaches 36616.8 Conclusions and future perspectives 367References 36817 HIF-1 Inhibitors for Cancer Therapy 377Annamaria Rapisarda and Giovanni Melillo17.1 Introduction 37717.2 Small molecule inhibitors of HIF- 1 37817.3 Exploiting HIF-1 inhibitors in combination strategies 39117.4 Conclusions 392Acknowledgements 392References 39318 Vascular-Targeted Molecular Therapy 401Graeme J. Dougherty and Shona T. Dougherty18.1 Introduction 40118.2 Approaches to targeting tumor vasculature in vivo 40318.3 Alternative targeting strategies 41218.4 Concluding remarks 413Acknowledgements 413References 413Index 421