Genomic Instability and Cancer Metastasis: Mechanisms, Emerging Themes, and Novel Therapeutic Strategies

252 Pages·2015·4.59 MB·English

by  Chris Maxwell, Cal Roskelley (eds.)

Cancer Metastasis - Biology and Treatment
Volume 20
Series Editors
Richard J. Ablin
Dept. of Pathology, University of Arizona College of Medicine,
Tucson, Arizona, USA
Wen G. Jiang
Institute of Cancer & Genetics Cardiff University,
Cardiff, United Kingdom
More information about this series at http://www.springer.com/series/5761
Chris Maxwell • Cal Roskelley
Editors
Genomic Instability
and Cancer Metastasis
Mechanisms, Emerging Themes, and Novel
Therapeutic Strategies
1 3
Editors
Chris Maxwell Cal Roskelley
Child & Family Research Institute Dept of Cellular & Physiological Sciences
University of British Columbia, Pediatrics University of British Columbia,
Vancouver Dept. of Cellular & Physiological Sciences
British Columbia Vancouver
Canada British Columbia
Canada

ISSN 1568-2102
ISBN 978-3-319-12135-2 ISBN 978-3-319-12136-9 (eBook)
DOI 10.1007/978-3-319-12136-9
Library of Congress Control Number: 2014956658
Springer Cham Heidelberg New York Dordrecht London
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Preface
In 1975, the mortality rate for all cancers in the United States was 199 deaths
per 100,000 people in the population [1]. The most recent statistics available
(2006–2010) indicate that the current mortality rate is 176.4 deaths per 100,000
people [2], which represents a modest 11 % reduction in the past 35 years. It has
been estimated that approximately 90 % of cancer deaths arise from the metastatic
spread of primary tumors [3]. Thus, any future improvement in the overall cancer
mortality rate will depend upon a more thorough understanding of the properties
that enable the metastatic process.
Cancers are diverse and complex tissues. Conceptually, it is proposed that
cancers possess shared hallmarks [4], but it may be more correct to consider can-
cer as an evolving, heterogeneous, and dynamic entity [5] that is responsive to a
plethora of selective events, both intrinsic to the tumor (e.g., hypoxia) and extrinsic
(e.g., combination chemotherapy). Within the framework of an evolving tissue, it is
clear that the extent of heterogeneity may provide selective advantages. Moreover,
scientists have long known that cancer cells display significant intra-tumoral het-
erogeneity at the genetic level [6], which falls under the umbrella term of genomic
instability. Therefore, it is reasonable to propose the interplay between tumor het-
erogeneity, which may be enabled by genomic instability, and an enhanced ability to
withstand the selection pressures applied throughout the metastatic process.
This book connects cancer metastasis with genomic instability in a comprehen-
sive manner through four sections. Section 1 outlines the fundamental mechanisms
that occur at tissue, cellular and molecular levels and regulate the processes of cancer
metastasis, genomic stability, and DNA damage response, respectively. Section 2
discusses the model systems that will enable our better understanding of the meta-
static process and genomic instability through experimentation performed in silico,
in vitro, and in vivo. Section 3 reviews emerging themes and frameworks for the
understanding of the contributions of non-tumor cells to the metastatic process (ex.,
tumor microenvironment, mechanotransduction, and immunomodulation). Finally,
Section 4 discusses new therapeutic approaches designed to overcome the unique
challenges presented by the heterogeneous and metastatic tumor.
Section 1 takes a reductionist approach to describe the mechanisms responsible
for the maintenance of tissue and cellular integrity starting with an examination of
v
vi Preface
the tumor tissue, followed by a discussion of processes that prevent instability at
the genome level, and ending with a discussion of molecular pathways that act at
the base-pair level to maintain integrity. Drs. Rodenhiser and Chambers (London
Regional Cancer Clinic, Canada) introduce the metastatic tumor as an evolving tis-
sue that presents many challenges, including diversity and dynamic heterogeneity,
which must be interrogated in the clinic if novel treatments are to be successful.
Dr. Connell and colleagues (University of British Columbia, Canada) outline the
pathways in the normal cell, or the malignant tumor cell, that are responsible for the
prevention of genomic instability and, when compromised, the promotion of het-
erogeneity. Dr. El-Khamisy and colleagues (University of Sheffield, UK and Helmy
Institute, Egypt) review the diverse molecular pathways that fall under the umbrella
term of the DNA damage response, and discuss the intimate relationship between
loss of function in each of these pathways and cancer predisposition.
More complete knowledge of cancer metastasis, and the complex interplay be-
tween regulators that are found in the cancer cell, the tumor tissue and within the
organism inflicted with cancer, will be born from studies that encompass in sili-
co, in vitro, and in vivo model systems, each of which are reviewed in Section 2.
Dr. Costes and colleagues (Lawrence Berkeley National Laboratories, USA) utilize
3D automated foci detection and computational modeling to understand and track the
properties and kinetics for repair of DNA double strand breaks. Chapter 4 outlines
how integration of mathematical models with irradiation data, a highly quantitative
and reproducible manner to induce DNA damage, enables the synthesis of new
knowledge in the fields of cancer initiation, detection and progression. In Chap-
ter 5, Dr. Bennewith and colleagues (BC Cancer Agency and Dalhousie University,
Canada) discuss a variety of animal models and the strengths and considerations
when using these models to address specific research questions, which span from
high-throughput analysis of novel compounds to dissection of the relative contribu-
tions of individual gene products during defined stages of cancer metastasis, from
local invasion to distal entrenchment and expansion.
In 2000, Hanahan and Weinberg outlined six hallmarks of cancer [7]; only one of
the six original hallmarks of cancer (i.e., they stimulate the growth of blood vessels
to supply nutrients to the tumor) identified a property that was extrinsic to the tumor
cell. It is increasing clear, however, that non-tumor cells, in the cancer tissue and
the patient afflicted with cancer, are critical to cancer progression and metastasis,
including, but not limited to, the role of tumor-stroma interactions and the tumor
microenvironment, mechanical cues provided from the environment to the tumor,
and immunomodulation. Section 3 reviews these emerging themes in the field of
tumor microenvironment and cancer metastasis. In Chapter 6, Dr. Calvin Roskelley
(University of British Columbia, Canada) provides an overview of microenviron-
mental control of cancer metastasis while recent advances in the fields of mechano-
transduction in the tumor and immunosurveillance are detailed by Dr. Nelson and
colleagues (Princeton University, USA) and Dr. Gregor Reid (University of British
Columbia, Canada) in Chapters 7 and 8, respectively.
Prevention and treatment of metastatic tumor spread may represent the most sig-
nificant challenge of medical oncology. In Chapter 8, Dr. Reid reviews the cross-talk
Preface vii
between immune cells and cancer cells; the controlled regulation of these dynamic
processes through chemical or cell-based therapies may allow for improved im-
munosurveillance of metastatic cells. While tumor heterogeneity enabled through
genome instability likely provides the tumor advantages against conventional che-
motherapeutic and irradiation treatments, it is hoped that molecular-targeted thera-
pies can turn the table by targeting pathways that are non-essential in normal tissue
but, due to the loss of parallel pathways, are essential to tumor cells. In Chapter 9,
Dr. McManus and colleagues (University of Manitoba, Canada) utilize colorectal
cancer as the framework within which to introduce the concept of synthetic le-
thality and review the recent therapeutic advances gained through the targeting of
deficient DNA repair pathways. Finally, a significant hurdle to the success of any
systemic therapy, including those that may eventually be used to combat metastatic
disease, is the efficient and specific delivery of the therapeutic agent to the target
cell or tumor. In Chapter 10, Drs. Hauser-Kawaguchi and Luyt (University of West-
ern Ontario, Canada) review the emerging field of nanomedicine and the utility of
nanoparticles for improved cancer imaging and drug delivery.
References
[1] Department of Health and Human Services (2010) Fact Sheet- Cancer. National Institutes of
Health. http://report.nih.gov/nihfactsheets/Pdfs/Cancer(NCI).pdf. Oct. 2010
[2] Howlader NNA, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl
J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds) SEER cancer
statistics review, 1975–2011. National Cancer Institute. Bethesda, MD. http://seer.cncer.gov/
csr/1975_2011, based on November 2013 SEER data submission, posted on the SEER web
site. April 2014.
[3] Christofori G (2006) New signals from the invasive front. Nature 441:444–450
[4] Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674
[5] Floor SL, Dumont JE, Maenhaut C, Raspe E (2012) Hallmarks of cancer: of all cancer cells,
all the time? Trends Mol Med 18:509–515
[6] Holland AJ, Cleveland DW (2009) Boveri revisited: chromosomal instability, aneuploidy and
tumorigenesis. Nat Rev Mol Cell Biol 10:478–87
[7] Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70
Contents
1 Cancer Metastasis: Tracking and Attacking a Moving Target .............. 1
David I. Rodenhiser and Ann F. Chambers
2 T he Generation, Detection, and Prevention of Genomic
Instability During Cancer Progression and Metastasis .......................... 15
Helen Chen, Christopher Maxwell and Marisa Connell
3 DNA Damage Response Pathways in Cancer Predisposition
and Progression .......................................................................................... 39
Mohamed E. Ashour, Lamia El-Shafie and Sherif F. El-Khamisy
4 Mathematical Modeling for DNA Repair, Carcinogenesis and
Cancer Detection ........................................................................................ 75
Jonathan Tang, Walter Georgescu, Thomas Deschamps,
Steven M. Yannone and Sylvain V. Costes
5 Animal Models of Metastasis .................................................................... 95
Dawn R Cochrane, Dong Lin, Graham Dellaire, Elizabeth
C Halvorsen, Jason N Berman, Yuzhou Wang, David G Huntsman
and Kevin L Bennewith
6 Microenvironmental Control of Metastatic Progression ........................ 125
Calvin D. Roskelley
7 Mechanotransduction, Metastasis and Genomic Instability .................. 139
Allison K. Simi, Alexandra S. Piotrowski and Celeste M. Nelson
8 Immunomodulation and Genomic Instability ......................................... 159
Gregor Reid
ix
x Contents
9 Synthetic Genetic Approaches in Colorectal Cancer:
Exploiting and Targeting Genome Instability ....................................... 179
Babu V. Sajesh, Amy L. Cisyk and Kirk J. McManus
10 Nanomedicine—Nanoparticles in Cancer Imaging and Therapy ....... 205
Alexandra M. N. Hauser-Kawaguchi and Leonard G. Luyt
Index .................................................................................................................. 245