Page 74 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 2 Tumor Biology and Metastasis 53

malignancies, including canine OSA. 146–149 The activity of MMPs ECM. 163 This phenomenon was termed anoikis, from the Greek
in OSA and mast cell tumors has been correlated with grade and word for homelessness. In normal tissues, anoikis is a mechanism
149,150
For the meta-
164
metastatic propensity.
for maintaining tissue homeostasis and integrity.
Similar correlative studies have been
VetBooks.ir undertaken in human patients. 151 The importance of MMP activ- static cancer cell, survival during dissemination requires resistance
ity during this early step in metastasis prompted the development
to anoikis. In normal tissues, anoikis is prevented by two systems:
of pharmacologic inhibitors of MMPs. Anticancer activity of these cell-matrix anchorage and cell-cell interactions. 165 Anchorage of
agents in preclinical animal models and in sporadic human patients cells to the ECM is mediated primarily by transmembrane recep-
was evident; however, in randomized trials, clinical benefit was not tors referred to as integrins. The formation of active heterodimers
observed. 152,153 The failure of these clinical trials may be explained triggers an intracellular cascade, resulting in activation of effec-
at many levels and does not refute the importance of invasion as tors of growth and survival. 166 Integrin family members have been
a critical step for a metastatic cell. Rather, these results suggest identified in canine sarcomas and lymphomas. 167–172 Cell-cell
potential redundancy in the types of invasion (mesenchymal versus anchorage in many epithelial tissues is mediated by cadherins, a
amoeboid) that may exist within a given cancer. 154,155 Recent evi- family of calcium-binding glycoproteins. Intracellularly, cadherins
dence also suggests that the expression of matrix-degrading enzymes form complexes with members of the catenin protein family that
and other growth factors may not be necessary in the tumor cells link them to the actin cytoskeleton, in addition to survival-pro-
themselves but may be provided by inflammatory cells (i.e., macro- moting signal transduction cascades. 173 Loss of either cell-cell or
phages) recruited by the growing tumor. 156 cell-matrix interaction in normal cells triggers the activation of the
caspase proteases, the hallmark of apoptotic cell death. Metastatic
Epithelial-Mesenchymal Transition cancer must resist this contact-dependent death to be successful
Observed primarily in the context of epithelial malignancies, the and must do so through two non–mutually exclusive mechanisms.
ability of tumor cells to engage in the early steps in the metastatic The first is by maintaining cell-cell contacts with other tumor cells
cascade has been linked to a transcriptional program referred to (homotypic interactions) or with host cells, such as platelets and
as EMT. 157 This transcriptional program has been largely ascribed inflammatory cells (heterotypic interactions), during metastatic
to the effects of a family of transcription factors, including twist, progression. Both homotypic and heterotypic interactions gen-
snail, and slug. 158 Activation of these and other EMT transcription erate intracellular signals that prevent the initiation of anoikis.
factors is not necessarily associated with a morphologic change in Additionally, cancer cells may overexpress proteins that directly
the cancer cell but may be associated with a loss of polarity (apico- inhibit anoikis. For example, the integrin pair α β is frequently
v 3
basal) in epithelial cells, a greater proportion of cells losing cell-to- overexpressed in malignancy, including prostate cancer and mela-
cell contacts similar to mesenchymal cells (observed in vitro), cell noma. 174,175 This overexpression subverts the need for ligand
motility, and invasion. In the “mesenchymal” state, suggested by binding and results in the generation of survival signals. 176 Pro-
EMT, epithelial cancer cells (similar to cells involved in embryo- teins reported to be involved in resistance to anoikis include tropo-
genesis) develop the phenotypic ability to undergo invasion, myosin receptor kinase B (TrkB), focal adhesion kinase (FAK, the
migration, and intravasation. 159 Interestingly, cells that are able immediate effector of integrin signaling), galectin-3, and TGF-
to take on these “mesenchymal” features share signaling programs β, among others. 177 Several other molecular mediators of anoi-
and other phenotypes with tumor-initiating cell populations. 160 kis resistance have been identified and are reviewed elsewhere. 178
Opponents of the EMT hypothesis are most critical of the use of These molecules may be valuable novel antimetastasis targets.
the term transition, which suggests a switch in the phenotype of indi-
vidual cells from an epithelial to a mesenchymal form. However, it Evasion of the Immune System
is reasonable and generally agreed that the effects of EMT transcrip-
tion factors contribute to the early phenotypes needed for metastatic At all stages of metastatic progression, metastatic tumor cells must
progression. Limited data also suggests a need for mesenchymal cells evade detection and destruction by the immune system. The abil-
to take on attributes of epithelial cells (likely later during metastatic ity of the host immune system to recognize and destroy tumor cells
progression) for successful metastasis, the so-called mesenchymal- (immunosurveillance) was first proposed by Paul Ehrlich in 1909.
epithelial transition (MET). For epithelial cancers MET is also Molecular support of the theory of immunosurveillance has come
understood to be a final step in EMT in which after the activation, with studies of mice deficient in immunomodulatory and proin-
development of an invasive phenotype, and colonization of a distant flammatory molecules, such as interferon-gamma (IFN-γ), inter-
site, cells will revert to their original epithelial phenotypes. leukin-12 (IL-12), and perforin. Mice deficient in these molecules
The process of intravasation concludes when a cancer cell success- are known to develop tumors more readily than wild-type mice.
80
fully enters the vascular or lymphatic circulation. Tumor cells may Clinical evidence for immunosurveillance against cancer was first
enter the circulation through established blood vessels, small arteri- reported by Coley more than 100 years ago. Through the admin-
oles, venules, or lymphatics, or through tumor-associated (or lined) istration of bacteria, Coley’s toxin, Coley was able to induce fever
161
blood vessels in a process referred to as vasculogenic mimicry. For and tumor regression in patients with cancer. Evidence in dogs
larger vascular structures the process of intravasation requires penetra- with OSA further supports the potential value of cancer immu-
tion of adventitial cells, including pericytes; digestion of the vascular notherapy. 179 Indeed, survival times in dogs developing bacterial
basement membrane; and penetration between or through EC. infection at the site of a limb salvage surgery are significantly lon-
162
Penetration of the tumor-associated vasculature may be easier than ger than in dogs that do not develop infection. Interestingly, simi-
invasion through normal vessels and may require only transit from lar parallels may be seen in human OSA patients. 180 It is believed
the extracellular environment between EC into the circulation. that in immunocompetent hosts, immunosurveillance removes a
large number of cancer cells from the primary tumor, from the
Survival in the Circulation (Resisting Anoikis) circulation, and at distant metastatic sites. Cancer cells use a wide
variety of mechanisms to effect this evasion. The mechanisms for
Frisch and Francis reported the induction of apoptosis after immunosurveillance and evasion of immunosurveillance by can-
disruption of the interaction between epithelial cells and the cer are reviewed elsewhere and are summarized in Chapter 14. 181