Page 76 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 2 Tumor Biology and Metastasis 55

patients is substantial. If true, the process of metastasis from differences may explain the more aggressive course of disease seen
metastases would suggest that all steps in the metastatic cascade in some dog breeds compared with others. Taken together, the risk
for metastatic progression is partly defined by the genetics of the
occur continuously, both before and after detection of metastases
VetBooks.ir in patients. As such, all of the steps in the metastatic cascade may patient, genetic changes that develop early in the process of tumor
development, and the subsequent and incremental emergence of
205–211
be targets for future therapeutic intervention.

aggressive metastatic cells.
Ongoing Controversies and Areas of Research in
the Field of Metastasis Where Is the Inefficiency in “Metastatic Inefficiency”?
As devastating as the metastatic process is, it is equally inefficient.
Does the Metastatic Propensity for Tumors Emerge Early or Estimates of this inefficiency in animal models suggest that less
Late in the Biology of Cancer? than 1% of cancer cells that successfully enter the circulation are
The development of the metastatic phenotype traditionally has able to survive at distant sites. 218 The true metastatic efficiency
been believed to be a process that happens late in carcinogene- of human cancers is likely to be much lower. In most studies to
sis. In this model, referred to as the progression model, the genetic date it does not seem that entry of cancer cells into the circula-
changes responsible for primary tumor development in most cases tion is the major barrier for successful metastases. Recent studies
are distinct and precede the steps that result in the metastatic phe- have identified high numbers of circulating tumor cells in cancer
notype. 212–213 The progression model argues that the metastatic patients who are free of metastatic disease. The clinical importance
phenotype is acquired within a small fraction of cells within the of high numbers of circulating tumor cells is not clear 219 ; however,
heterogeneous primary tumor. Support for the progression model for some cancers high numbers of circulating cancer cells appar-
came from work by Fidler and others, who demonstrated the abil- ently do not necessarily correlate with the risk for metastasis. But-
ity to select for rodent cancers with greater metastatic potential, ler and Gullino estimated that 1 to 4 × 10 cells/g of tumor enter
6
through the serial passage of metastatic tumor nodules back to the systemic circulation each day in human cancers. 220 This data
naïve mice. This selection phenomenon suggested that a minor- suggests that, although intravasation is necessary for metastasis, it
ity of tumor cell clones within a primary tumor were endowed is not sufficient nor is it process limiting. After removal of the pri-
with the metastatic phenotype and that this small proportion were mary tumor, these circulating cell counts drop, and in many cases
enriched in the metastases compared with the primary tumor. no gross metastases develop. Although arrest at target organs may
Application of the progression model would suggest that a period be a limitation for some cancers, early survival of cancer cells at
exists between primary tumor development and acquisition of the distant sites appears to be a major hurdle for successful metastases
full metastatic phenotype. This model was thought to be the basis and therefore is a significant contributor to metastatic inefficiency.
of the improved outcome associated with early detection of can- Metastatic cancer cells appear to be highly vulnerable to death
cers and the belief that effective and definitive therapy was most early after their arrival at a secondary site. The microenvironment
likely if a diagnosis was made early. Work from Ramaswamy et al of the secondary site is distinct from that of the primary tumor site
provided data to support an alternative model, “the early onco- and the initial tissues of origin of the cancer cell. These differences
genic model” for metastasis. 214–217 This alternative suggests that include changes in oxygen tension, pH, growth factor availability,
the genetic events that contribute to initial primary tumor devel- and cellular binding partners. Collectively, these changes represent
opment are the same or emerge at the same time as the events that unique stressors to metastatic cancer cells. 221
contribute to the metastatic phenotype. As such, the early onco- Metastatic cells must recognize, adapt, and endure these stresses
genic model suggests, the biology of a cancer is defined early and to survive. Furthermore, appropriate modulation of the secondary
may not be something that can be reduced through early identifi- microenvironment before the cancer cells arrive (premetastatic
cation of a cancer. This is not to say that early detection of a cancer niche) and as a result of early and effective interaction with stromal
is not helpful for a patient, but rather that bad cancers may be and inflammatory cells within the new environment allow select
“born” bad. This model may explain the phenomenon of “meta- populations of cells to survive and proliferate. The duration of this
static carcinoma of unknown primary site,” in which metastatic initial vulnerable state during metastatic progression may extend
disease is detected without an apparent primary tumor. for the entire period of dormancy (see later). Also, metastatic cells
To add complexity to the question of the emergence of the likely must pass successfully through additional vulnerable states
metastatic phenotype, increasing evidence indicates that host later during metastatic progression. Targeting metastatic cancer
(genomic) differences can influence the metastatic behavior of can- cells during these vulnerable states may be an effective treatment
cers without necessarily influencing primary tumor growth. 214,215 strategy for cancer metastasis. 222
Using a genetically engineered mouse model of mammary cancer,
Hunter et al have been able to identify specific host genes that What is Dormancy and Where Do Dormant Cells Reside?
influence metastatic behavior of tumors. 214–217 These findings In spite of effective control of the primary tumor and aggres-
have several important implications. First, they suggest that indi- sive multiagent and multimodality adjuvant therapy, the risk for
viduals might be predisposed to aggressive metastatic progression metastases to distant sites remains high for several cancer histolo-
before the development of a tumor. In addition they suggest that gies. Because most patients are free of gross metastases at the time
some families in the population may be at high risk, not neces- of diagnosis, the development of metastases is presumed to emerge
sarily for tumor development, but for an aggressive metastatic from microscopic cells that are not identifiable at the time of initial
course once a tumor develops. Most important, if a significant patient presentation. 223 The location, size, angiogenic state, and
part of a patient’s metastatic risk is encoded within the patient’s proliferative/apoptotic state of these microscopic cells are largely
constitutional genome rather than within the mutated tumor unknown. Indeed, these dormant cells may exist as single cancer
genome, it may be feasible to identify individuals at high risk for cells or microscopic clusters; they may exist in a quiescent (outside
metastatic disease at the time of diagnosis of the primary tumor, or the cell cycle) or balanced state of proliferation and apoptosis; they
potentially before. This finding may be particularly relevant in the may lie dormant in the eventual secondary metastatic tissue site
field of veterinary oncology, in which breed-associated genomic (e.g., the lung); or they may persist in sanctuary sites (e.g., the