Page 75 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

54 PART I The Biology and Pathogenesis of Cancer

Modification of the immune system to treat cancer and prevent leukocyte trafficking and function. In metastasis chemokines may
metastasis continues to be an attractive therapeutic strategy. 182 also contribute to the metastatic process through enhanced meta-
Chemokines may be active in the recruit-
198
Clinical trials based on this concept have been reported through-
static cell survival.
VetBooks.ir out the veterinary literature in dogs with melanoma, soft tissue ment of a leukocytic infiltrate to intravasated, circulating tumor
sarcoma, hemangiosarcoma, OSA, and others, using a variety of
cells, therein creating an embolus that can better resist shearing
immune-based therapies. 185 This principle has been the basis for stress associated with circulation or through the generation of
the development and approval of a therapeutic vaccine directed matrix-degrading proteins at the distant metastatic site.
against a melanoma antigen in dogs with melanoma. 186
The Premetastatic Niche and Modulation of the
Arrest in Target Tissues Microenvironment
The arrest of circulating tumor cells at distant sites is thought to It is increasingly clear that the sites (microenvironments) of suc-
occur by two distinct but potentially overlapping mechanisms. cessful secondary metastasis are modulated by the presence of a
These include size-dependent “trapping” of tumor cells within the primary tumor and then by the arrival of metastatic cells at the sec-
lumens of small vessels (capillaries and veins) in the target organ, ondary site. The concept of the premetastatic niche suggests that
and/or receptor-mediated interaction involving the tumor cell and a primary tumor modulates the microenvironment of a secondary
the host vasculature. 187 Data supporting the trapping phenom- site before the arrival of most metastatic cells. 199 The modulation
enon comes from single-cell imaging studies in which metastatic of the premetastatic niche appears to be accomplished by primary
cancer cells were observed to arrest primarily at distant vascular tumor–induced mobilization and recruitment of specific, primar-
beds as a result of size-dependent restrictions of large tumor cells ily bone marrow–derived cells (bone marrow niche) to the sec-
in small blood vessels. 188,189 This work was conducted primar- ondary microenvironment. 200 These bone marrow–derived cells
ily for metastasis to the liver and more recently for metastasis to are myeloid in origin and express VEGFR. Interestingly, the sites
the brain. 190 This trapping phenomenon suggests that the site for of metastatic tumor arrest appear preferentially to include sites
metastasis from a primary tumor is guided largely by the location in which these myeloid-derived cells were first recruited. Further-
of the first (small vessel) vascular bed encountered by a tumor more, targeting these VEGFR-positive cells using pharmacologic
cell. Alternatively, several groups have suggested the role of spe- and genetic tools has effectively prevented metastatic development
cific adhesion molecules as being necessary for initial tumor arrest in murine models. 201 Ongoing studies likely will uncover greater
in the microenvironment of the secondary metastatic sites. 191–193 complexity of the populations of cells recruited to the premeta-
Both of these mechanisms likely play a role in the initial seeding static niche and potentially therapeutic targets for antimetastatic
of distant metastatic target organs. The dominant mechanism of therapy.
arrest may be primarily defined by tumor type or target organ. After survival at the distant site, the tumor cell must proliferate
and modulate its new environment. In most cases cancer cells are
Early Survival at Distant Sites believed to extravasate from the circulation and then proliferate
in the new organ. However, proliferation also may occur within
Once the cancer cell or cancer embolus has arrested at its dis- blood vessels, in a process referred to as intravascular metastases,
tant sites, it may immediately move out of the circulation into and then expand into the local tissue before further proliferation
the target organ or may stay within the circulation. 194 In either occurs. 201 In both situations modulation of the new environ-
location the cancer cell must survive in a new microenvironment. ment is necessary for appropriate growth and progression of the
Early survival of metastatic cells at secondary sites is a significant metastatic lesions. We now recognize that part of this modulation
hurdle for the cancer cell. Several studies have shown the ability is based on tumor-induced changes in the stroma. 202,203 These
of cancer cells to arrest at multiple organs in the body. Within stromal changes may result in the production of growth factors
hours the number of remaining cells is reduced dramatically, and or signals that are used by the tumor for further growth. These
within days the number of viable cells may be as low as 0.1% of stromal cell–derived growth factors provide important signals for
the original number of cells, even for the most aggressive cancer tumor cell proliferation and progression, including angiogenesis.
models. 195 To a large extent organ selectivity for cancers is defined The importance of tumor-stromal interaction suggests that the
by the organs in which a cancer cell can survive after initial arrest. “induced” tumor-stroma may be a credible target for novel cancer
The “seed and soil” hypothesis first articulated by Paget and then therapeutics. 204
more recently by Fidler et al 193,213 suggests that the success of a
cancer, or metastasis, is defined by interactions between the seed Metastasis from Metastases
(tumor cell) and the soil (the tumor microenvironment). 196
Arrest of tumor cells in target organs may or may not be recep- For most solid tumors the appearance of a single metastatic nod-
tor mediated (discussed earlier); however, adhesion requires recep- ule is followed shortly by the development of additional metas-
tor-ligand interactions. Contributors to these steps include the tases within the same target organ and tertiary sites. All these
cell adhesion molecules (CAMs). Multiple CAMs have been iden- metastatic sites are unlikely to emerge from distinct and unique
tified and are named based on their cell specificity (e.g., N-CAM clones within the primary tumor and nearly simultaneously prog-
for neural and L-CAM for liver). CD44 is a specific adhesion ress through the metastatic cascade to yield synchronous metasta-
molecule (H-CAM for homing) initially identified as the receptor ses at the distant site. It is reasonable, and perhaps more likely, that
for the matrix component hyaluronic acid on hematopoietic cells. metastases develop from other metastatic sites. In this hypothesis
Expression of splice variants of CD44 on tumor cells has been a small number of successful clones colonize distant sites. As these
demonstrated to correlate with a poor prognosis in a wide vari- clones move through progression to become successful metastases,
ety of human tumors, from acute myelogenous leukemia (AML) the process of metastasis continues, resulting in metastasis from
and Hodgkin’s disease to breast and colon cancer and OSA. 197 metastases. Although data supporting this hypothesis is limited,
Chemokines are a class of chemotactic cytokines that function in the implication for the treatment and management of cancer