Page 73 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

52 PART I The Biology and Pathogenesis of Cancer

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• Fig. 2.9 The metastatic cascade. The metastatic cascade describes a set of discrete steps that cells
must move through as a part of the process of metastasis. This complexity begins with the recognized
complexity associated with primary tumor development, in which tumor cells must proliferate, resist apop-
tosis, and develop interactions with many host cells in the microenvironment. Subsequent steps allow
metastatic cancer cells to enter and survive in the circulation. Cells then arrest at distant locations, extrava-
sate, and survive in the microenvironment of the distant locations. Arrest of cells may be at the eventual
secondary organ where metastasis becomes clinically evident, or cells may initially arrest at a “sanctuary
site,” where they may lie dormant before moving on to the eventual secondary site. The cellular programs
that result in a break of dormancy are not well understood. Survival of cells at these sites of dormancy or
the eventual secondary site is a significant hurdle for metastatic cells to overcome. Indeed, the majority
of cells that arrive at distant locations are unable to survive in these distant locations. At secondary sites,
tumor cells may proliferate and progress after the development of the angiogenic phenotype. It is likely
that successful metastatic lesions at secondary sites are then the source of subsequent metastases within
these secondary sites.

Metastasis suppressor genes have been identified in several human to invade and intravasate include the classic model of enzymatic deg-
cancers. These genes also are thought to have normal functions in the radation of the ECM referred to as mesenchymal invasion (see later
regulation of motility, invasion, and angiogenesis. The loss of these discussion on EMT). Unlike in mesenchymal invasion, tumor cells
genes is not thought to be associated with the formation of tumors; may also develop so-called amoeboid invasion, in which they individu-
however, their loss is thought to contribute to specific steps in the ally slip between fibers of the ECM without evidence or a need for
metastatic cascade. The characterization, biology, and clinical effect of enzymatic degradation. Finally, a distinct method, termed collective
140
metastasis suppressor genes have been recently reviewed elsewhere. invasion, refers to the en masse regional extension of a tumor into
136
The loss or reduced expression of metastasis suppressors has not been surrounding tissues. Such collective invasion is observed clinically
141
documented in canine or feline cancers to date. in dogs with oral SCC and biologically high-grade/histologically low-
The succeeding sections provide descriptions of the critical grade fibrosarcoma. The low rate of distant metastasis associated with
metastasis-associated processes (see Fig. 2.9). Examples of genetic collective invasion suggests a lack of functional attributes necessary for
changes or resulting protein changes that contribute to each process true distant metastasis. It is likely that individual metastatic tumors
are highlighted in each section, with particular emphasis on those may use distinct invasion programs at distinct points during meta-
with demonstrated associations with veterinary malignancies. static progression. Not surprisingly, studies with intravital imaging
(single cell imaging of cancer cells in animals) have demonstrated that
Intravasation only a minority of the cells in the primary tumor develop any of these
forms of invasion. 142,143 Efforts are underway to define the genetic
After the successful growth of the primary tumor, intravasation of features of this minority population. 144,145
a cancer cell into the vascular or lymphatic circulation is the first In the classic mesenchymal form of invasion, matrix proteases
necessary step in the metastatic cascade. The process of intravasation and metalloproteases (MMPs) are believed to be necessary for the
requires that a tumor cell be motile and able to digest, modulate, or invasive phenotype. Expression of members of this enzyme fam-
escape the ECM. 137–139 The specific mechanisms used by cancer cells ily has been found in most human and several canine and feline