Page 32 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 1 The Etiology of Cancer 11

Sphere forming cell
Non-sphere forming cell 1st sphere 2nd sphere
Bulk tumor cells
VetBooks.ir

Gain
High SFE group More proliferating progenitor cells
ACSL1 (down)
ACSL5 (down)
FASN (up)
Fatty acid synthesis ↑
Immunosuppressive cytokines ↑
Steady
Low SFE group More quiescent or self-renewing cells

ACSL1 (up)
ACSL5 (up)
FASN (down)
Fatty acid oxidation ↑
CD40 upregulating immune evasion ↑
• Fig. 1.6 A proposed model of cancer cells showing their distinct capacity to form and maintain spheres.
(Reproduced with permission from Kim JH, Frantz AM, Sarver AL, et al. Modulation of fatty acid metabo-
lism and immune suppression are features of in vitro tumor sphere formation in ontogenetically distinct
dog cancers. SFE, sphere-forming efficiency. Vet Comp Oncol. 2018 March;16(1):E176-E184. https://doi.
org/10.1111/vco.12368. Fig. 1.5.)

However, it was apparent that multipotent stem cells were present would be more consistent with a stochastic model. The prevailing
in this tumor population. In 1994 Dick’s group proved conclu- opinion is that CSCs exist and are characterized both by peculiar
sively that another type of leukemia, acute myelogenous leukemia phenotypes and defined sets of mutations of a small number of
(AML), was a hierarchically organized disease in which a small genes. 116–118 Other mutations then endow their progeny with a
number of cells undetectable by conventional methods could be limited or an extensive capacity to undergo programmed differ-
isolated from patients and made to recapitulate the full spectrum entiation, thus resulting in the distinct clinical phenotypes that
of the disease in an animal model. 113 This gave rise to the CSC, characterize acute and chronic leukemias or high-grade and low-
or “tumor-initiating cell,” hypothesis, which is based on the con- grade solid tumors.
cept that tumors are hierarchically organized into a subpopula- In companion animals, progenitor cells with putative CSC or
tion of cells that retain or acquire the capacity for self-renewal tumor-propagating properties have been identified in HSA, OSA,
and are capable and responsible for initiating and maintaining brain tumors, and possibly lymphoma. 119–122 These cells appear to
the tumor. 114 Another subpopulation of cells that consists of the rely on metabolic and immune reprogramming to regulate their
CSC progeny undergo partial to complete differentiation and lose self-renewal and differentiation programs (Fig. 1.6). 89
the capability to support the tumor, albeit still contributing to As is true for the rest of cancer genetics, information in this
the morbidity of cancer. This hypothesis fundamentally altered field is rapidly evolving. Large-scale bioinformatics and concep-
the way cancer is understood, but it also gave rise to a debate tual advances are integrating the CSC theory into the mainstream
about how widely this model applies. In the competing hypoth- of cancer research and biology, and also into the design for new
esis, commonly referred to as the stochastic model, all the cells in diagnostic and therapeutic strategies. For example, it appears that
a tumor have an equal capacity for self-renewal. According to this much like hematopoietic stem cells, the CSC niche favors oligo-
model, the process of cancer is driven entirely (or almost entirely) clonality and some genetic diversity. Thus clonal competition can
by environmental selection of favorable mutations; this model ensue, giving rise to heterogeneous tumors and maintaining a res-
necessarily would predict that cancer is an inevitable outcome for ervoir of cells that can reestablish the tumor when a therapy effec-
multicellular organisms, and few, if any, long-lived animals would tively kills the predominant CSC clone and its progeny. Similarly,
reach reproductive age. 115 Thus, by necessity, this model must clonal competition can facilitate distant spread by selection of cells
invoke the existence of protective mechanisms independent of the with different capabilities. An extreme example may be the poten-
cancer risk (e.g., efficient DNA repair mechanisms and immune tial for a single tumor cell (or a small population of oligoclonal
surveillance). cells in a tumor) to give rise to histologically distinct tumors—an
The two models may represent a continuum dependent on event that has been observed in xenotransplanted sarcomas.
the extent to which CSCs undergo asymmetric versus symmetric
divisions. Under conditions in which CSC divisions are primar- Recent Advances in Canine Cancer Genetics
ily asymmetric, few CSCs would be apparent and the population
would achieve a hierarchical organization; under conditions in An important conceptual advance in canine cancer genetics was
which CSCs underwent symmetric divisions, virtually every cell in the identification of conserved (homologous) aberrations in spon-
the tumor would have CSC-like properties and the organization taneous dog tumors that had been previously characterized in