Page 191 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster
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balanced translocations, deletions, and cytogenetic mani- Carcinogenesis: A Multistep Process 177
festations of gene amplification. Furthermore, it is well established that over a period of
• Balanced translocations contribute to carcinogenesis by time, many tumors become more aggressive and acquire
overexpression of oncogenes or generation of novel greater malignant potential. This phenomenon is referred
fusion proteins with altered signaling capacity. Deletions to as tumor progression and is not represented simply by an
frequently affect tumor suppressor genes, whereas gene increase in tumor size. Careful clinical and experimental
amplification increases the expression of oncogenes. studies reveal that increasing malignancy often is acquired
• Overexpression of miRNAs can contribute to carcino in an incremental fashion. At the molecular level, tumor
genesis by reducing the expression of tumor suppressors, progression and associated heterogeneity are most likely
while deletion or loss of expression of miRNAs can lead to result from multiple mutations that accumulate inde
to overexpression of proto-oncogenes. pendently in different cells, generating subclones with dif
• Tumor suppressor genes and DNA repair genes also may ferent characteristics (Fig. 5–17) such as ability to invade,
be silenced by epigenetic changes, which involve revers rate of growth, metastatic ability, karyotype, hormonal
ible, heritable changes in gene expression that occur not responsiveness, and susceptibility to antineoplastic drugs.
by mutation but by methylation of the promoter. Some of the mutations may be lethal; others may spur cell
growth by affecting proto-oncogenes or cancer suppressor
CARCINOGENESIS: A MULTISTEP genes. Thus even though most malignant tumors are monoclonal
PROCESS in origin, by the time they become clinically evident their con-
stituent cells may be extremely heterogeneous.
Carcinogenesis is a multistep process resulting from the
accumulation of multiple genetic alterations that collec During progression, tumor cells are subjected to immune
tively give rise to the transformed phenotype. Many cancers and nonimmune selection pressures. For example, cells
arise from non-neoplastic precursor lesions, which molecu that are highly antigenic are destroyed by host defenses,
lar analyses have shown already possess some of the muta whereas those with reduced growth factor requirements
tions needed to establish a full-blown cancer. Presumably are positively selected. A growing tumor, therefore, tends
these mutations provide the cells of the precursor lesion to be enriched for subclones that “beat the odds” and
with a selective advantage. Once initiated, cancers continue are adept at survival, growth, invasion, and metastasis.
to undergo darwinian selection. Finally, experience has shown that when tumors recur after
chemotherapy, the recurrent tumor is almost always resis
As discussed earlier, malignant neoplasms have several tant to the drug regimen if it is given again. This acquired
phenotypic attributes, such as excessive growth, local inva resistance, too, is a manifestation of selection, as subclones
siveness, and the ability to form distant metastases. that by chance bear mutations (or perhaps epigenetic alter
ations) imparting drug resistance survive and are respon
sible for tumor regrowth. Thus, genetic evolution and selection
can explain two of the most pernicious properties of cancers: the
tendency for cancers to become (1) more aggressive and (2) less
responsive to therapy over time.
Tumor cell Requiring fewer
variants growth factors
Nonantigenic
Normal Carcinogen- Tumor Invasive
cell induced cell Metastatic
change Human solid
malignancy
Clonal
expansion
of surviving
cell variants
TRANSFORMATION PROGRESSION PROLIFERATION TUMOR CELL
OF GENETICALLY VARIANTS:
UNSTABLE CELLS
HETEROGENEITY
Figure 5–17 Tumor progression and generation of heterogeneity. New subclones arise from the descendants of the original transformed cell by
multiple mutations. With progression, the tumor mass becomes enriched for variants that are more adept at evading host defenses and are likely to
be more aggressive.
