Page 71 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

50 PART I The Biology and Pathogenesis of Cancer

is in contrast to a reductionist view of cancer biology, which con- tumor-initiating cell, and in other tumors the initiating cell may
siders the tumor just a mass of tumor cells. In reality, the tumor is be the resident progenitor or transit-amplifying cell. A character-
istic of the CSCs is that they undergo asymmetric division and
a complex system containing cancer cells and supporting cells, all
VetBooks.ir of which contribute to the maintenance of the malignant popu- self-renew, providing a continual resident population of highly
resistant cancer cells.
lation and support ultimate dissemination and metastasis. The
major players in the cancer “organ system” are: Existing cancer therapies have been largely developed against
• Cancer cells and cancer stem cells (CSCs) the bulk population of tumor cells because they are often identi-
• Endothelial cells fied by their ability to shrink tumors. Because most cells within
• Pericytes a cancer have limited proliferative potential, an ability to shrink
• Immune cells a tumor mainly reflects an ability to kill these cells. It seems that
• Tumor-associated fibroblasts normal stem cells from various tissues tend to be more resistant
to cytotoxic therapy than mature cell types from the same tissues.
Cancer Cells and Cancer Stem Cells If the same is true of CSCs, then one would predict that these
cells would be more resistant to cytotoxics than tumor cells with
The concept that a cancer can arise from any cell in the body, limited proliferative potential. Even therapies that cause complete
along with the stochastic model of tumorigenesis, has recently regression of tumors might spare enough CSCs to allow regrowth
been challenged. 104–107 Although tumor heterogeneity is a well- of the tumors. Therapies that are more specifically directed against
established concept, a new dimension to heterogeneity has been CSCs might result in much more durable responses and even cures
established that suggests that a tumor may contain a hierarchical of metastatic tumors. In veterinary oncology putative stem cell
structure similar to many normal organ systems. Recent evidence populations have been identified for breast, bone, brain, and liver
suggests the existence of CSCs (sometimes termed tumor-initiating tumors. 104–107,118–120 Interestingly, stem cell populations appear
cells), which form the founder cell population for a tumor. to have altered DNA repair pathways, which may explain their
It was first extensively documented for leukemia and multiple resistance to conventional drugs. Identification of these popula-
myeloma that only a small subset of cancer cells are capable of tions, coupled with the availability of microarray and microRNA
extensive proliferation. For example, when mouse myeloma cells array technology, is allowing the identification of potential thera-
were obtained from mouse ascites, separated from normal hema- peutic targets.
topoietic cells, and put in in vitro colony-forming assays, only 1 in Recent research has linked the acquisition of CSC characteris-
100 to 1 in 10,000 cancer cells were able to form colonies. Even tics with the EMT program, described subsequently in the section
when leukemic cells were transplanted in vivo, only 1% to 4% of on metastasis. 120 Cells that undergo EMT also take on character-
cells could form spleen colonies. 106–114 Because the differences in istics reminiscent of the CSC phenotype. For example, they have
clonogenicity among the leukemia cells mirrored the differences the ability to self-renew and may support the ability of cells to
in clonogenicity among normal hematopoietic cells, the clono- colonize outside of the primary tumor. One may speculate that
genic leukemic cells were described as “leukemic stem cells.” the signaling processes that support EMT may also serve to main-
It has also been shown for solid cancers that the cells are phe- tain the CSC population within a tumor and may also suggest
notypically heterogeneous and that only a small proportion of plasticity in CSC populations.
cells are clonogenic in culture and in vivo. 114–117 For example,
only 1 in 1000 to 1 in 5000 lung cancer, ovarian cancer, or Endothelial Cells
neuroblastoma cells were found to form colonies in soft agar.
Just as in the context of leukemic stem cells, these observations Much of the heterogeneity in tumors is found in the stromal com-
led to the hypothesis that only a few cancer cells are actually partment, and many of these cells are EC, which form the tumor-
tumorigenic and that these tumorigenic cells could be consid- associated vasculature. VEGF and basic fibroblast growth factor
ered CSCs. Although the field and concept of CSCs is a con- are two prominent signaling molecules in the formation of these
troversial one, CSCs may prove to be a common constituent of vessels. More modern sequencing techniques also have identified
many, if not all, cancer types. Features of the CSC model also fit new pathways that may represent important signaling systems
well with a view of metastasis in which only a small number of for neoangiogenesis and may represent therapeutic targets (e.g.,
cells within a tumor have the ability (and plasticity) to endure Notch signaling). 121
the stresses of metastatic progression, survive during a dormant
period, and then progress, proliferate, and differentiate into the Pericytes
complex heterogenous metastatic lesion.
If tumor growth and metastasis are driven by a small population Pericytes are mesenchymal cells that wrap around the endothelial
of CSCs, this might explain the failure to develop therapies that are tubing of the blood vessels. Pericytes are considered a major cell
consistently able to eradicate solid tumors. 104–107 Although cur- type supporting the tumor vasculature. 122
rently available drugs can shrink tumors, these effects are usually
transient and often do not appreciably extend the life of patients. Immune Inflammatory Cells
One reason for the failure of these treatments is the acquisition of
drug resistance by the cancer cells as they evolve; another possibil- As described previously, an environment of chronic inflammation
ity is that existing therapies fail to kill CSCs effectively. is an important enabling characteristic that supports the acquisi-
Stem cell populations have been identified in human breast, tion of cancer-related traits. Cells of the innate immune system
bone, brain, colon, pancreas, liver, ovary, and skin cancers. 108–112 are particularly crucial for the maintenance of the tumor envi-
The actual origin of CSCs within solid tumors has not been ronment. In particular, tumor macrophages with a specific protu-
clarified and may actually vary among tumor types. In some mor phenotype can enhance cellular proliferation, invasion, and
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tumors the resident adult or somatic stem cell may serve as the neoangiogenesis.