Page 192 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

178 C H A P T E R 5 Neoplasia
HALLMARKS OF CANCER
This overview serves as background for a more detailed
consideration of the molecular pathogenesis of cancer and
the carcinogenic agents that inflict genetic damage. In the
past 30-some years, hundreds of cancer-associated genes
have been discovered. Some, such as TP53, are commonly
mutated; others, such as ABL, are affected only in certain
leukemias. Each cancer gene has a specific function, the
dysregulation of which contributes to the origin or progres­
sion of malignancy. It is best, therefore, to consider cancer-
related genes in the context of several fundamental changes
in cell physiology, the so-called hallmarks of cancer, which
together dictate the malignant phenotype. Six of these are
illustrated in Figure 5–18:
• Self-sufficiency in growth signals
• Insensitivity to growth inhibitory signals
• Evasion of cell death
• Limitless replicative potential
• Development of sustained angiogenesis
• Ability to invade and metastasize
To this list may be added two “emerging” hallmarks of
cancer, reprogramming of energy metabolism and evasion
of the immune system, and two enabling characteristics,
genomic instability and tumor-promoting inflammation.
Mutations in genes that regulate some or all of these
cellular traits are seen in every cancer; accordingly, these
Evading Self-sufficiency in
apoptosis growth signals
Insensitivity to
anti-growth signals
Sustained Tissue invasion
angiogenesis and metastasis
Limitless replicative
potential
Figure 5–18 Six hallmarks of cancer. Most cancer cells acquire these
properties during their development, typically by mutations in the rele-
vant genes.
(From Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100:57, 2000.)
traits form the basis of the following discussion of the
molecular origins of cancer. Of note, by convention, gene
symbols are italicized but their protein products are not
(e.g., RB gene and Rb protein, TP53 and p53, MYC and
MYC).
Self-Sufficiency in Growth Signals
Cancer cells use a number of strategies to drive their pro­
liferation and become insensitive to normal growth regula­
tors. To appreciate these phenomena, it is helpful to review
briefly the sequence of events that characterize normal cell
proliferation (introduced in Chapter 2). Under physiologic
conditions, cell proliferation can be readily resolved into
the following steps:
1. The binding of a growth factor to its specific receptor
on the cell membrane
2. Transient and limited activation of the growth factor
receptor, which in turn activates several signal-
transducing proteins on the inner leaflet of the plasma
membrane
3. Transmission of the transduced signal across the cytosol
to the nucleus by second messengers or a cascade of
signal transduction molecules
4. Induction and activation of nuclear regulatory factors
that initiate and regulate DNA transcription
5. Entry and progression of the cell into the cell cycle,
resulting ultimately in cell division
The mechanisms that endow cancer cells with the ability to
proliferate can be grouped according to their role in the
growth factor–induced signal transduction cascade and
cell cycle regulation. Indeed, each one of the listed steps is
susceptible to corruption in cancer cells.
Growth Factors
All normal cells require stimulation by growth factors to
undergo proliferation. Most soluble growth factors are
made by one cell type and act on a neighboring cell to
stimulate proliferation (paracrine action). Normally, cells
that produce the growth factor do not express the cognate
receptor. This specificity prevents the formation of positive
feedback loops within the same cell.
• Many cancer cells acquire growth self-sufficiency by
acquiring the ability to synthesize the same growth
factors to which they are responsive. For example, many
glioblastomas secrete platelet-derived growth factor
(PDGF) and express the PDGF receptor, and many sar­
comas make both transforming growth factor-α (TGF-α)
and its receptor. Similar autocrine loops are fairly
common in many types of cancer.
• Another mechanism by which cancer cells acquire
growth self-sufficiency is by interaction with stroma. In
some cases, tumor cells send signals to activate normal
cells in the supporting stroma, which in turn produce
growth factors that promote tumor growth.
Growth Factor Receptors and Non-Receptor
Tyrosine Kinases
The next group in the sequence of signal transduction is
growth factor receptors, and several oncogenes that result
from the overexpression or mutation of growth factor