Page 67 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

46 PART I The Biology and Pathogenesis of Cancer

also likely to operate in cancer cells and may be as important as apoptotic mechanisms). Basic molecular and pathologic studies of
some of the autonomous mechanisms of tumor growth. It recently tumors have confirmed that acquired resistance toward apoptosis
and other types of death is a hallmark of all types of cancer.
was suggested that growth signals for the proliferation of carcinoma
VetBooks.ir cells are derived from the tumor stromal elements (e.g., cancer- or tance to cell death and apoptosis. One of the most common ways
Cancer cells, through a variety of strategies, can acquire resis-
carcinoma-associated fibroblasts [CAFs]). It is therefore possible
that the survival of tumor cells not only relies on the acquisition of is through loss of function of the TS protein p53. Removal of nor-
growth signal autonomy, but also may require the recruitment or mal p53 function leads to failure of the cells’ sensor mechanism
modulation of stromal cells to provide these growth signals. for DNA damage. When the cell suffers an insult, such as UV
radiation, hypoxia, or exposure to DNA-damaging agents, signals
Insensitivity to Antigrowth Signals or Evading are funneled through p53 to cause either cell cycle arrest or apop-
tosis. Failure of this mechanism can contribute to the progression
Growth Suppressors of the cell toward malignancy and promote the accumulation of
Within the normal cell multiple antiproliferative signals operate to additional genetic defects that are not corrected at defined check-
maintain cellular quiescence and homeostasis. These signals include points in cell cycle progression. 59
soluble growth inhibitors that act via cell surface receptors and The mechanisms involved in apoptosis are now well estab-
immobilized inhibitors that are embedded in the ECM and on the lished, as are the strategies by which cancer cells evade its actions.
surface of nearby cells. The signals operate to push the cell either However, recently conceptual advances have been made involv-
into G0 or into a postmitotic state (usually associated with the ing other forms of “programmed cell death” as a barrier to can-
acquisition of specific differentiation–associated characteristics) and cer development. A notable example is the emerging role that
thus are intimately associated with cell cycle control mechanisms. autophagy plays in cancer development. Autophagy is a normal
Cells monitor their external environment during the progression cellular response that operates at low basal levels in cells but can
through G1 and, on the basis of external stimuli, decide whether be induced in states of cellular stress, such as nutrient deficiency.
to proliferate, become quiescent, or enter into a postmitotic state. In autophagy controlled breakdown of cellular organelles yields
Most cellular programs that negatively regulate cell growth energy and cellular substrates that can be used for a variety of cel-
and proliferation depend on the actions of TS genes. At the basic lular functions. Recent evidence suggests that autophagy may be
level most of the antiproliferative signals are funneled through the involved in both tumor cell survival and, paradoxically, tumor cell
Rb protein and its close relatives. Disruption of Rb allows cell death, depending on the cellular state. The link between apopto-
proliferation and renders the cell insensitive to antiproliferative sis and autophagy suggests that autophagy may represent another
signals, such as that provided by the well-characterized transform- barrier for cells to overcome before they can attain malignancy. In
ing growth factor-β (TGF-β). The Rb protein integrates signals contrast, it has also been shown that irradiation or cytotoxic drug
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from diverse extracellular and intracellular sources and can control treatment in late-stage tumors may promote autophagy, leading to
cell cycle progression. The other major TS is p53, which integrates cells attaining a state of reversible dormancy. The situation seems
intracellular signals and can promote either cell cycle arrest or to suggest that autophagy is a barrier to tumor development in
apoptosis (depending on the degree of cellular stress or damage). early disease, but in late-stage disease may allow cancer cells to
However, the effects of p53 expression are highly context depen- survive severe cellular stress. 77,78
dent. Loss of Rb or p53 is associated with the malignant pheno- In both autophagy and apoptosis the process does not lead
type through the cell’s ability to evade antigrowth signals. to the release of any “proinflammatory” signals. In contrast, the
In addition to TS gene loss, cells can evade antigrowth signals process of necrosis, observed in larger tumors, causes release of
by alternative cellular programs: signals that support an influx of inflammatory cells. For many
• Evasion of contact inhibition. Cell-to-cell contact in most years this has been considered a positive event, helping expose the
normal cells results in an inhibitory signal against further immune system to tumor antigens and promote immune destruc-
cell proliferation. The role of this mechanism in vivo has tion. However, recent evidence suggests that some phenotypes of
been thought to be to maintain tissue homeostasis. In inflammatory macrophages can actually support tumor growth
cell culture contact inhibition is abrogated in cancer cell through fostering of angiogenesis, cancer cell proliferation, and
monolayers, leading to their indefinite expansion. NF2 and invasion. Consequently, our understanding of macrophage phe-
LKB1 genes are considered tumor suppressor genes that are notypes in cancer progression is an area of active research. 79,80
involved in this process, and loss of these genes in vivo may
promote loss of contact inhibition that contributes to the Limitless Replicative Capacity
progression of cancers. 75
• Although TGF-β has antiproliferative effects in cancer, it is More than 30 years ago the pioneering observations of Hayflick
now appreciated that the TGF-β pathway can be corrupted in established that when normal human or animal cells are grown in
the later stages of malignancy and can contribute to cancer pro- culture, they demonstrate a finite replicative life span. That is,
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gression. 76 they are capable of a finite number of cell divisions, after which
• In this late effect TGF-β is found to activate a cellular program they undergo what has been termed replicative senescence and are
termed epithelial-to-mesenchymal transition (EMT) that pro- incapable of any further cell division. The mechanism underly-
motes invasion and metastasis (see the following discussion). ing the replicative clock that monitors this process has been the
subject of intense research. This process has further evoked con-
Evading Cell Death: The Roles of Apoptosis, siderable interest because it is also one of the mechanisms that
must be overcome to establish the “immortal” phenotype that is
Autophagy, and Necrosis characteristic of the cancer cell. 69,70
The growth of any tumor depends not only on the rate of cell divi- In mammalian cells DNA is organized into chromo-
sion, but also on the rate of cellular attrition (mainly provided by somes within the nucleus, and these are capped by specialized