Page 72 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 2 Tumor Biology and Metastasis 51

Cancer-Associated Fibroblasts
in dormancy, cells receive signals to proliferate, create new blood
vessels (angiogenesis) or co-opt existing blood vessels, and then
Cancer-associated fibroblasts make up the supporting structure
VetBooks.ir for many tumors but can also promote invasion, cell prolifera- successfully grow into a measurable metastatic lesion. Further
47
tion, and neoangiogenesis. The importance of the various cell
progression likely is associated with the repetition of this process,
types that make up the TME cannot be overstated. Although a resulting in the development of metastases from metastases. As
complex signaling network exists between and within cancer cells such, the steps outlined here continue not only after the detection
that maintains the cancer phenotype, superimposed on this are of the primary tumor, but also after the detection of metastases.
the complex signaling networks between stromal components and From a therapeutic perspective, therefore it is never too late to
cancer cells. Although the potential evolution of cancer cells from target the biologic steps associated with metastatic progression as
early disease to late-stage disease has been discussed, it is quite a means to improve outcomes for patients. The basic tenets of this
possible that a similar evolution occurs in the supporting struc- model of metastasis have been intact for more than 40 years; how-
tures, dictated by the cancer itself. For example, incipient tumors ever, a greater understanding of the biologic principles associated
may recruit stromal elements, which reciprocate by promoting cell with each metastatic process is emerging. 124
proliferation and angiogenesis. Evolution of the cancer population
may then feed back on the stromal population to further repro- Metastasis-Associated Genes and Metastasis
gram these cells to support the growing tumor. Of course, this
could be extended to show the role of the stroma in promoting Suppressor Genes
invasion and metastasis. These mechanisms underpin the com- Cancer cells are not unique in their ability to complete the individual
plexity of understanding cancer pathogenesis, because the process steps required for metastasis (Fig. 2.9). For example, leukocytes and
is highly dynamic and context dependent. 123 neuronal cells have the ability to invade tissue planes and cross vascu-
lar barriers. Several types of leukocytes demonstrate the phenotype of
Key Points intermittent adherence to vascular endothelium and are able to resist
anoikis. It is also true that stem cells of various phases of differentia-
• Cancer arises through multiple molecular mechanisms under- tion are able to perform many of these steps during development and
pinned by changes at the genetic and/or epigenetic level. in the adult. 125,126 Metastatic cells are unique in that each cell must
• Cancer has been defined as the acquisition of eight fundamen- be able to perform all the steps required for successful metastasis. An
tal characteristics shared across multiple cancer types. These extension of this argument is that the genetic changes that permit the
hallmarks are enabled and supported by underlying genomic metastatic process are not unique to a metastatic cancer cell; however,
instability and tumor-associated inflammation. the metastatic cell must have the appropriate set of genetic changes
• The normal circuitry in cells is reprogrammed to support these available to complete all the steps of the metastatic cascade.
hallmarks and drive tumor progression. Literally hundreds of genes and their resultant proteins have
• These circuits are interconnected and are also supported by been suggested to contribute to the development of cancers and
cross-talk from cells making up the tumor microenvironment. to their eventual ability to metastasize. A single genetic change
• Cancer stem cells may play a major role in maintaining the in cancer can contribute many of the metastasis-associated pro-
tumor in a way similar to the maintenance of normal organ cesses (e.g., metastasis super enhancer), or several genes can work
systems by adult stem cells. together toward a single metastasis-associated process. Metastatic
cancers may achieve the metastatic phenotype through distinct
The Process of Tumor Metastasis constellations of genetic and epigenetic events that in their respec-
tive sums complete the list of necessary metastasis-associated pro-
Metastasis is defined as the dissemination of neoplastic cells to cesses needed for successful metastasis. 127
discontinuous secondary (or higher order) sites, where they pro- Two classes of genes have been broadly defined as contributing
liferate to form a macroscopic mass. Implicit in this process is the to the metastatic phenotype. These include metastasis promoting
presence of a primary tumor. Metastases are not a direct exten- genes 128,129 and metastasis suppressors. 129,130 These genes have func-
sion of the primary tumor and are not dependent on the route tions in normal development and physiology (i.e., cell migration, tis-
of spread (i.e., hematogenous versus lymphatic versus peritoneal sue invasion, and angiogenesis, discussed earlier) that are subverted by
dissemination). The process of metastasis is believed to occur the cancer cell in the acquisition of the metastatic phenotype.
through the completion of a series of step-wise events. For this The use of high throughput and genome-wide investigations
process to occur, a cancer cell must leave the site of the primary has uncovered many putative metastasis-associated genes in can-
tumor, pass through the tumor basement membrane, and then cer. It should be noted that many metastasis-associated genes
through or between endothelial cells to enter the circulation have functions that also contribute to tumor formation and pro-
(extravasation). While in the circulation, tumor cells must be able gression. Several of these metastasis-associated genes have been
to resist anoikis (programmed cell death associated with loss of validated in canine and feline cancers. 131,132 For example, the
cellular contact), evade immune recognition and physical stress, metastasis-associated gene ezrin was identified using genomic
and eventually arrest at distant organs. At that distant site the cell approaches in murine and human studies of metastasis. 133 Ezrin
must leave the circulation and survive in the hostile microenviron- is a membrane-cytoskeleton linker protein that functionally and
ment of the foreign tissue. These secondary sites are believed to be physically connects the actin cytoskeleton to the cell membrane.
primed to receive metastatic cells through effects that are directed The degree of ezrin expression in the primary tumor of dogs with
and mediated by the primary tumor itself (premetastatic niche). osteosarcoma (OSA) was shown to predict a more aggressive
The distant site may be the eventual target organ for metastasis course of disease, defined by metastasis to the lung. Furthermore,
or may be a temporary (sanctuary) site. In either case, the can- recent studies have confirmed the connection between ezrin and
cer cell is thought to lie dormant for a variable and often pro- protein kinase C (PKC) signaling in murine, canine, and human
tracted period before moving to its final location. After a break OSA cells. 134,135