Page 28 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 1 The Etiology of Cancer 7

disabling some of the intrinsic advantages this dysfunction pro- Thus dogs with HSA and OSA provide an opportunity to test
vides for cancer cells and allowing better penetration of drugs. therapeutic inhibition of the CXCR4-CXCL12 axis as a means
to delay or prevent metastasis. (Chapter 2 presents additional
(Chapter 15, Section C, provides additional information about
VetBooks.ir antiangiogenic therapies.) information about basic mechanisms and treatments to manage
Angiogenesis takes center stage in malignant vascular tumors
cancer metastasis.)
such as hemangiosarcoma (HSA), which occurs commonly in
dogs. Malformed, disorganized vascular structures composed of Genomic Instability and Mutation
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a mixture of malignant and nonmalignant cells are the defining
feature of canine HSA and human angiosarcomas. Among other The concept of genomic instability is not new, but it was incor-
proangiogenic drivers, canine HSAs show elevated production of porated as an “enabling hallmark” into the updated Hanahan
VEGF, 54–56 IL-8, and sphingosine-1 phosphate (S1P) and its and Weinberg model. Traditionally, stepwise clonal evolution
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receptor, S1P1 . Furthermore, the magnitude of the angiogenic provided a satisfactory explanation of tumor progression because
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drive is associated with somatic mutations of angiopoietin, VEGF, it could be correlated with discrete pathologic changes. This is
and PI3K signaling pathways, in addition to the biologic behavior especially true for epithelial tumors, in which such progression
of the tumors. 42,59 This data suggests that canine HSA may pro- can be appreciated in lesions that go through stages of hyperpla-
vide a powerful, spontaneous model for unraveling critical events sia, atypical hyperplasia (dysplasia), adenoma, carcinoma in situ,
that control tumor angiogenesis. invasive carcinoma, and metastatic carcinoma. However, analy-
sis of tumor genomes, even in early stages, usually shows aneu-
Activating Invasion and Metastasis ploidy (an abnormal DNA copy number), in addition to chaotic
changes indicative of multiple numeric and structural DNA
The role of genetic events in invasion and metastasis is still incom- abnormalities. Similar abnormalities, first noticed by Boveri
pletely understood. The classic model of metastasis proposed by more than 100 years ago in studies of sea urchin cells, led him
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Fidler suggests a stepwise acquisition of assets that enables cells to to formulate the “aneuploidy theory” of cancer. Aneuploidy
leave the primary tumor site, travel through the blood or lymph, now is known to be especially evident in solid tumors; based on
invade stroma in favorable locations, and thus become reestab- this, Loeb proposed the existence of the “mutator phenotype,”
lished at distant sites. Other research suggests that most tumors in which cells are predisposed to undergo multiple mutations,
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have the ability to dislodge cells that travel to distant sites, and some of which inevitably lead to cancer. Some tenets of his
the ability of such cells to survive in capillary beds may be the hypothesis appear to be correct, although perhaps through dif-
most important step in the metastatic process. 61–65 A systematic ferent mechanisms than those envisioned by Loeb, as they might
assessment of metastasis reveals that it is a complicated process relate to increased activity of polymerases with low fidelity under
partly controlled by tumor heterogeneity and in which genetically conditions in which the rate of DNA damage (and consequently
distinct cells contribute to the dissemination of tumor cells from mutations) is higher than the expected background from normal
primary sites to metastatic sites (Fig. 1.4). 66 DNA replication (e.g., in lung epithelial cells from heavy smok-
BMDCs have intrinsic properties that allow them to travel ers). However, direct measurements of mutation rates of spo-
throughout the body, traffic through all major organs, and home radic tumors are much lower than those predicted if a “mutator
to areas of inflammation. Thus bone marrow–derived tumors are phenotype” was operative in these tumors. Indeed, the mini-
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inherently metastatic. Nevertheless, hematopoietic tumors that mum number of “critical” or driver mutations required for the
are cytologically indistinguishable can have distinct and preferen- clinical onset of cancer in solid tumors, based on sequencing of
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tial tissue distribution. The events that make leukemic cells stay solid tumor genomes, probably is on the order of 15 to 25.
in the peripheral circulation are not yet fully understood, even However, this may apply mainly to tumors with chaotic karyo-
though cells from corresponding lymphomas or myeloid sarco- types, because the number of mutations identified in a cytoge-
mas, with virtually identical molecular signatures, stay confined to netically stable leukemia was significantly smaller. 33
lymphoid or visceral organs. Still, genetic instability is a hallmark of most tumors, and
In epithelial neoplasms that account for most tumors in although it can be partly explained by increased errors in DNA
humans, the epithelial-to-mesenchymal transition (EMT) has replication and chromosomal segregation in cells that are rapidly
received increasing attention for its role in metastasis. It remains dividing, other mechanisms are clearly operative, involving telo-
unclear whether EMT is equally important in the sarcomas more meres and telomerase. 73,75–79 Although many of these changes are
commonly seen in domestic animals, in which the cells of origin not “recurrent” and appear to be random products of instability,
seem to retain EMT capabilities to a greater extent. Increasing some may in fact contribute to a proliferative crisis. This is con-
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evidence indicates that interactions between cancer cells, includ- sistent with Tomasetti and Vogelstein’s observation that initiation
ing both the “initiating” population in the tumor (colloquially events for many tumors occur early in life, during highly prolif-
referred to as cancer stem cells, or CSCs), and the remainder erative stages of tissue growth and remodeling, but they become
(bulk) of tumor cells and other cells in the tumor microenvi- evident later in life when one or a few critical mutations allow the
ronment, including mesenchymal stem cells (MSCs), CAFs, transformed cell to reach this crisis stage.
inflammatory cells, and angiogenic cells, may be responsible for
cancers’ invasive behaviors and for their ability to survive in hos- Tumor-Promoting Inflammation
tile environments at distant (metastatic) sites. One example is
signaling through the CXCR4-CXCL12 axis, which contributes The role of inflammation in cancer has received considerable
to the metastatic process through interactions between tumor attention in the past 20 years. Although our understanding of
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cells and the tumor-permissive niche. CXCR4 is upregulated this phenomenon remains incomplete, it clearly met the criteria
recurrently in canine HSA and OSA, 68–70 where it is presumed for inclusion as an “enabling hallmark” in the updated Hanahan
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to promote invasion and migration upon binding CXCL12. and Weinberg model. The importance of inflammation was