Preface xiii
List of Contributors xv
1 The Microenvironment in Cancer 1
Nicole N. Parker and Dietmar W. Siemann
1.1 Introduction 1
1.2 A highly selective process is required to obtain the cancer phenotype 1
1.3 The cancer phenotype 2
1.4 The extracellular matrix 3
1.5 Motility, invasion, and metastatic ability 4
1.6 Impact of the tumor microenvironment on the control of cancer 4
1.7 Targeting the tumor microenvironment 5
1.8 Summary 5
References 6
2 Establishing the Tumor Microenvironment 7
Allison S. Betof and Mark W. Dewhirst
2.1 Introduction 7
2.2 From cancerous cells to a tumor 8
2.3 A tumor is more than cancer cells and fibroblasts 9
2.4 Communication between the tumor cells and stroma 11
2.5 Hypoxia and angiogenesis 12
2.6 Conclusion 24
Acknowledgements 24
References 24
Further reading 33
3 Contributions of the Extracellular Matrix to Tumorigenesis 35
Marie Schluterman Burdine and Rolf A. Brekken
3.1 The extracellular matrix 35
3.2 Manipulation of the ECM during tumor development 38
3.3 Matricellular proteins and their complex effects on tumor development 39
3.4 Conclusion 47
References 48
4 Matrix Metalloproteinases and Their Inhibitors - Friend or Foe 53
Mumtaz V. Rojiani, Marzenna Wiranowska and Amyn M. Rojiani
4.1 Introduction 53
4.2 Matrix metalloproteinases 54
4.3 Tissue inhibitors of matrix metalloproteinases 63
4.4 Concluding comments 69
References 69
5 Role of Tumor-Associated Macrophages (TAM) in Cancer Related Inflammation 77
Antonio Sica and Chiara Porta
5.1 Introduction 77
5.2 Functional plasticity of macrophages 77
5.3 Macrophages as key orchestrators of cancer-related inflammation 79
5.4 Recruitment and differentiation of TAM 81
5.5 Protumoral functions of TAM 83
5.6 Molecular determinants of TAM functions 87
5.7 Therapeutic targeting of TAM 89
5.8 Conclusions 91
References 92
6 Bone Marrow Stroma and the Leukemic Microenvironment 99
William B. Slayton and Zhongbo Hu
6.1 Introduction 99
6.2 Components and function of the normal bone marrow microenvironment 99
6.3 Leukemia and its microenvironment 119
6.4 Summary 123
References 124
7 Microenvironment Factors Influencing Skeletal Metastases 135
Alessandro Fatatis, Julia A. D'Ambrosio, Whitney L. Jamieson, Danielle L. Jernigan and Mike R. Russell
7.1 Introduction 135
7.2 The bone microenvironment as a target for cancer cell dissemination 136
7.3 Roles of the bone microenvironment in promoting the arrest of circulating cancer cells at the skeleton 137
7.4 Concluding remarks 153
References 153
8 Premetastatic Niches 161
Kevin L. Bennewith, Janine T. Erler and Amato J. Giaccia
8.1 Introduction 161
8.2 'Seeds' influencing the 'Soil' 162
8.3 Cellular components of premetastatic niches 164
8.4 ECM components of premetastatic niches 166
8.5 Premetastatic niche formation precedes metastatic growth 170
8.6 Therapeutic targeting of the premetastatic niche 172
8.7 Evidence for premetastatic niches in the clinic 174
8.8 Concluding remarks 174
References 175
9 Hypoxia, Anerobic Metabolism, and Interstitial Hypertension 183
Michael F. Milosevic
9.1 Introduction 183
9.2 Pathophysiology of the tumor microenvironment 184
9.3 Evaluating the tumor microenvironment 189
9.4 Biologic and therapeutic implications 195
9.5 Clinical implications 199
9.6 Summary 201
References 201
10 Hypoxia and the DNA Damage Response 207
Isabel M. Pires, Rachel Poole and Ester M. Hammond
10.1 Introduction 207
10.2 The DNA damage response 208
10.3 Hypoxia regulation of DNA repair 215
10.4 Context synthetic lethality: exploiting hypoxic deregulation of DNA repair 220
10.5 Conclusions 221
References 221
11 Non-Invasive Imaging of the Tumor Microenvironment 229
Bénédicte F. Jordan and Bernard Gallez
11.1 Introduction 229
11.2 Imaging tumor vasculature, perfusion, and angiogenesis 229
11.3 Imaging tumor hypoxia: chronic and acute 234
11.4 Imaging tumor oxygen consumption 240
11.5 EPR oximetry 240
11.6 Imaging tumor interstitial fluid pressure (IFP) 244
11.7 Imaging tumor pH 245
11.8 Imaging tumor redox status 248
11.9 Imaging tumor response 250
11.10 Optimizing therapeutic intervention using molecular imaging 256
11.11 Conclusions 261
References 261
Further reading 270
12 Hypoxia-Inducible Factor 1 (HIF1) Mediated Adaptive Responses in the Solid Tumor 271
Tereza Goliasova and Nicholas C. Denko
12.1 Introduction 271
12.2 Molecular consequences of tumor hypoxia 272
12.3 Hypoxia inducible factor 1 273
12.4 HIF-1 subunits and domain structure 273
12.5 Regulation of HIF-1¿ protein stability and activity by post-translational modifications 274
12.6 HIF isoforms 275
12.7 Oxygen-independent HIF signaling 276
12.8 HIF target genes 277
12.9 Hypoxia and oxygen delivery 279
12.10 Hypoxia and glucose metabolism 280
12.11 Hypoxia and acidosis 281
12.12 Hypoxia and metastasis 282
12.13 Therapeutic implications 283
References 285
13 Regulation of the Unfolded Protein Response in Cancer 291
Jing Zhang and Albert C. Koong
13.1 Introduction 291
13.2 The UPR signaling cascade 292
13.3 Hypoxia activates UPR 295
13.4 UPR and expression of UPR-targeted genes in cancer 298
13.5 Concluding remarks 304
References 304
14 Influence of Hypoxia on Metastatic Spread 311
Richard P. Hill and Naz Chaudary
14.1 Introduction 311
14.2 The metastatic process 313
14.3 The tumor microenvironment and metastasis 316
14.4 Summary 326
References 326
15 Drug Penetration and Therapeutic Resistance 329
Andrew I. Minchinton and Alastair H. Kyle
15.1 Introduction 329
15.2 Tumor microenvironment 330
15.3 Drug penetration 334
15.4 In vitro tumor models 338
15.5 Conclusions 346
References 347
16 Impact on Radiotherapy 353
Michael R. Horsman, Jens Overgaard and Dietmar W. Siemann
16.1 Introduction 353
16.2 The tumour vasculature and microenvironment 353
16.3 Influence of tumor hypoxia on radiation therapy 356
16.4 Reducing hypoxia by increasing oxygen delivery 358
16.5 Radiosensitizing hypoxic cells 363
16.6 Killing the resistant cell population 365
16.7 Vascular targeting approaches 366
16.8 Conclusions and future perspectives 367
References 368
17 HIF-1 Inhibitors for Cancer Therapy 377
Annamaria Rapisarda and Giovanni Melillo
17.1 Introduction 377
17.2 Small molecule inhibitors of HIF- 1 378
17.3 Exploiting HIF-1 inhibitors in combination strategies 391
17.4 Conclusions 392
Acknowledgements 392
References 393
18 Vascular-Targeted Molecular Therapy 401
Graeme J. Dougherty and Shona T. Dougherty
18.1 Introduction 401
18.2 Approaches to targeting tumor vasculature in vivo 403
18.3 Alternative targeting strategies 412
18.4 Concluding remarks 413
Acknowledgements 413
References 413
Index 421
