Page 30 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 1 The Etiology of Cancer 9

activated oncogenes and/or by loss of tumor suppressor genes, immunoediting, in which the immune system destroys strongly
providing cancer cells with selective growth and survival advan- antigenic tumor cells, providing weakly antigenic cells a survival
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advantage. Experimental evidence for this concept includes
tages by conferring the hallmark capabilities of cell proliferation,
VetBooks.ir avoidance of cytostatic controls, and attenuation of apoptosis. differences between tumors grown in immunocompetent mice
(only weakly antigenic tumors survive) and immunocompro-
The reliance of cancer cells on glycolysis can be further accentu-
ated under hypoxic conditions. In fact, Warburg-like metabolism mised mice (no selection against strongly antigenic tumors is
seems to be present in rapidly dividing embryonic tissues, suggest- observed), but evidence only now is emerging that will allow us
ing a role in supporting large-scale biosynthetic programs that are to understand the importance of immunoediting in spontaneous
required for active cell proliferation. cancers.
Cancer cells do not seem to enable the Warburg effect univer- That the tumor microenvironment forms and maintains an
sally. Rather, much like other cells with high energetic demands, immunosuppressive barrier provides more compelling evidence
they seem to sort out into lactate-secreting (Warburg) and lactate- for the role of the immune system in limiting tumor growth
consuming cells, providing an efficient, albeit homeostatically and metastasis. 91,92 This immunosuppressive barrier includes
disturbed, energy environment. Furthermore, it seems that oxy- cellular factors, such as regulatory T cells (T ), myeloid-
regs
genation is not static in tumors, but instead fluctuates temporally derived suppressor cells (MDSCs), and MSCs. Soluble fac-
and regionally as a result of the instability and chaotic organiza- tors, including transforming growth factor-β (TGF-β) and
tion of tumor-associated neovasculature. Altered energy metabo- immunoglobulins, also contribute to the immunosuppressive
lism is proving to be as widespread in cancer cells as in many of the barrier directly and indirectly. This is an active area of basic
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other cancer-associated traits that have been accepted as hallmarks and clinical research in which companion animal oncology has
of cancer. This realization raises the question of whether deregu- been at the forefront; for example, through the generation and
lating cellular energy metabolism is a core hallmark capability of approval of the first active gene-based therapeutic cancer vac-
cancer cells that is as fundamental as the six well-established core cine for canine melanoma. 94
hallmarks. In fact, the redirection of energy metabolism is largely A transformational advance in cancer therapy has been the
orchestrated by proteins that are involved in one way or another ability to block immune checkpoints that are engaged by a num-
in programming the core hallmarks of cancer. When viewed in ber of tumors—particularly those that have unstable genomes
this way, aerobic glycolysis is simply another phenotype that is and tend to generate greater numbers of neoantigens (Fig.
programmed by proliferation-inducing oncogenes, and the desig- 1.5). 95,96 Antibodies against cytotoxic T lymphocyte-associated
nation of reprogrammed energy metabolism as an emerging hall- protein 4 (CTLA-4), and against programmed cell death pro-
mark seems most appropriate. tein 1 (PD-1) and its corresponding ligand, programmed death-
It is worth noting that this characteristic of tumor cells provides ligand 1 (PD-L1), aim to reactivate tumor-specific T cells and
at least one important diagnostic advantage. Upregulation of the cause a robust antitumor immune response. 97,98 The remarkable
major glucose transporter, GLUT-1, is seen in virtually all tumors, responses observed in patients receiving immune checkpoint
making the cells efficient glucose scavengers. This can be exploited to blockade as adjunctive or first-line therapy have made this class
image tumor cells precisely and noninvasively by visualizing glucose of compounds part of the standard of care for several types of
uptake using positron emission tomography (PET) with a radiola- lung cancer, malignant melanoma, renal cell carcinoma, Hodg-
beled analog of glucose ( F-fluorodeoxyglucose, or F-FDG) as kin lymphoma, head and neck squamous cell carcinoma, urothe-
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a reporter. The combination of PET with computed tomography lial carcinoma, certain colon cancers, and certain liver cancers.
(PET-CT) now is one of the most robust means to evaluate com- Checkpoint inhibitors currently are being tested in canine
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position of tumors, minimal residual disease, and tumor-specific clinical trials ; expression of canine PD-L1 has been detected
objective responses in patients receiving conventional and experi- in a number of canine tumor types, including mastocytoma,
mental therapies, and it increasingly is being applied to improve the melanoma, renal cell carcinoma, and several others. 100 Canine
diagnosis and staging of dogs with cancer. 86–88 CTLA-4 has been identified and cloned, 101 and although canine
In addition, evidence is accumulating that deregulated cellu- anti–CTLA-4 has not yet been developed, an agonistic recom-
lar energetics contribute to tumor progression through immuno- binant canine CTLA-4 molecule has been successfully used to
modulation. Our group has proposed a model in which cancer induce tolerance in a transplant model. 102 (Chapter 14 presents
cells’ self-renewal is causally related to reprogramming of fatty additional information about cancer immunotherapy.)
acid metabolism and immune signaling ; this supports the
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notion that fate decisions of tumor-initiating or stem cells rely
on cellular metabolism and immunomodulation in the tumor Adaptive Evolution and the Tumor
microenvironment. Microenvironment

Avoiding Immune Destruction A bidirectional flow of information occurs between the tumor and
the microenvironment, with each helping to mold the other into
Burnet and Thomas proposed the concept that the immune sys- functional growing tissue that can evade or withstand attack by
tem can recognize and destroy incipient tumors (cancer immu- the host. 103 The previous reference to a “selective growth advan-
nosurveillance) in the 1950s. Their hypothesis was far ahead of tage” that is reminiscent of darwinian selection is not acciden-
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its time, and technologic obstacles impeded proof, so the theory tal. The clonal evolution theory 104 addresses the significance of
fell into disfavor. In recent years the immunosurveillance theory sequential genetic changes providing growth and survival advan-
has gained traction anew because data strongly suggest that the tages; however, to this must be added the fact that, in addition
immune system helps to keep tumors at bay, and thus tumors to these self-sufficient events that influence growth and survival,
must evade the immune response to survive. In its recent incar- tumor cells must also evade “predators” (e.g., inflammation and
nation, the theory has been refined to incorporate the concept of the immune system). 90,105 In essence, the interaction of the tumor