Page 69 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

48 PART I The Biology and Pathogenesis of Cancer

signals that result in EC survival, motility, invasion, differentia- observation that the Warburg effect also can be detected in grow-
tion, and organization. These steps are required to create a sup- ing cells in the embryo. An expansion of the theory of reprogram-
ming of energy metabolism in cancer suggests that cancer cells
portive vasculature for the tumor. In many ways these required
VetBooks.ir endothelial processes share parallel features with the processes have an advantage in a flexibility in their ability to derive ATP.
This may come from a number of metabolic pathways that derive
required for the success of a metastatic cancer cell itself. The cre-
ation of new blood vessels requires the tumors to recruit circulating ATP from glucose metabolism under aerobic and anaerobic con-
EC to their site, presumably through the release of growth factors, ditions, but it may also include efficiencies in metabolizing amino
such as vascular endothelial growth factor (VEGF). Circulating acids and lipids toward ATP and other biomolecule synthesis.
EC must survive at their new site with the help of survival signals Such metabolic flexibility may be necessary during primary tumor
and form vascular tubes that then reorganize to sustain blood flow. development, but even more so during metastatic progression (see
The resulting vasculature of cancers is typically aberrant with often next section).
poorly organized and chaotic vascular structures that are leaky,
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with limited adventitial development and excessive branching. Evading Immune Destruction
Once developed, this angiogenic phenotype (the result of the
angiogenic switch) is associated with a diverse pattern of ongoing It is well defined that primary tumors and metastatic lesions can
angiogenesis and neovascularization. This ongoing process is likely elicit both protective and suppressive immune responses. 79–80 B
complex and involves a wide variety of tumor and microenviron- cells serve the host by the production of tumor-reactive antibod-
mental-derived growth factors and signaling molecules. Adding ies. However, these antibodies may help define tumor-specific
to this complexity, certain phases of cancer progression likely are antigens (TSA) and aid in diagnosis, but they tend not to be
associated with and require periods of antiangiogenesis. Indeed, protective for the host. Intense research has proven that the most
these hypovascularized states may directly contribute to the pro- protective forms of immunity against cancer are provided by the
gression of certain cancers. Regulation of angiogenesis depends cell-mediated arm of the immune system, and immunocompro-
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on the balance between proangiogenic and antiangiogenic factors. mised animals are at increased risk of tumor development. (Tumor
There is controversy as to the exact biologic function of thrombo- immunology is covered in detail in Chapter 14.)
spondin-1 (TSP1) in angiogenesis. Although some studies suggest The current and long-standing theory suggests that the cellular
that TSP1 promotes neovascularization, TSP1 is commonly rec- and tissue environment is constantly sampled and monitored by
ognized as an endogenous angiogenesis inhibitor. 96 the immune system. 100 If a tumor is “altered self,” then this should
Many lines of evidence support the importance of angiogenesis lead to eradication by a functioning immune system. Although
in the biology of metastasis. The vascularity of a primary tumor there is a strong body of evidence to suggest that the immune
(measured by microvessel density) has been correlated with meta- system plays a major role in creating a barrier to tumor formation
static behavior for most human and many veterinary tumors. The and progression, it is clear that when cancer arises, there is a fail-
expression of angiogenesis-associated growth or survival factors ure of either surveillance or elimination mechanisms or both. 100
and their receptors (i.e., VEGFR) in serum and in tumors, respec- Epidemiologic evidence suggests that even the most immunogenic
tively, has also been correlated with outcome; more recently func- tumors have the ability to evolve mechanisms to subvert an appar-
tional imaging studies using magnetic resonance imaging (MRI) ently functioning immune system. This may arise through mul-
and other means has provided correlates of vascularity with poor tiple mechanisms, but the best characterized of these include 101 :
outcome. 97,98 The strength of this biologic argument has sup- • Inhibition of the effects of infiltrating cytotoxic T cells or
ported the development of a number of novel therapeutic agents natural killer (NK) cells
with antiangiogenic activities. These agents have moved through • Recruitment of immunosuppressive inflammatory cells
discovery and development and are now approved drugs for can- (regulatory T cells [Treg] or myeloid-derived suppressor
cer. Additional information regarding angiogenesis and antiangio- cells (MDSC) and tumor-promoting macrophages
genic therapy is provided in Chapter 15, Section C. • Defective antigen presentation; for example, by downregu-
lation of the MHC class-1 machinery in cancer cells
Reprogramming Energy Metabolism • Failure of cancer cells to express co-stimulatory molecules,
creating anergy or tolerance
The sustained growth and proliferation of a cancer requires a • Expression of “immune checkpoint molecules,” such as
corresponding adjustment of energy metabolism to ensure this CTLA-4, or programmed-death-1 ligand/receptor (PD/
growth can be fueled. Under normal conditions, cells respire aer- PDL-1), which inhibit T-cell function
obically in that they metabolize glucose to pyruvate with a net
gain in energy as ATP. Cancer cells can undergo a “metabolic Tissue Invasion and Metastasis
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switch” so that glucose is metabolized to lactate, in the presence or
absence of oxygen, causing a net energy deficit. A corresponding The process of invasion and metastasis is covered in detail in sub-
upregulation of glucose transporters (e.g., GLUT-1) occurs, which sequent sections of this chapter.
increases the uptake of glucose into the cytoplasm. This process
is exploited in positron-emission tomography (PET) imaging The Enabling Characteristics
because tumors preferentially uptake a radiolabeled analog of glu-
cose ( F-fluorodeoxyglucose [FDG]). This metabolic switch is As previously suggested, the hallmarks of cancer have been defined
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sometimes referred to as the Warburg effect (Fig. 2.8). 99 as functional capabilities that allow cancer cells to survive, prolif-
It is difficult to appreciate the survival advantage of this mecha- erate, and disseminate. The fact that these critical hallmarks can
nism. One hypothesis is that the switch allows the diversion of be attained within a single cancer is explained by two key enabling
glycolytic intermediates into other biosynthetic pathways that characteristics of cancer – genome instability and tumor-promot-
support the production of new cells. This is supported by the ing inflammation.