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Carcinogenesis: Mechanisms and Models Chapter | 20 343

VetBooks.ir Tumor Promotion Is a Nongenetic Process
That Affects the Growth Kinetics of the Initiated
Cells and It Can Be Reversible
Tumor promoters alter the expression of genetic infor-
mationofthe cell andinmanycasesinhibitpro-
grammed cell death (Pitot, 2002). Tumor promoters are
involved in mitogenic signaling to trigger increased cell
proliferation, thereby influencing the proliferation of
initiated cells as well. Irigaray and Belpomme (2010)
defined tumor promoters as nongenotoxic carcinogens
capable of causing clonal expansion of initiated cells,
i.e., able to induce proliferation of mutated cells and to
prevent these cells from apoptotic loss, so the possibility
of additional genetic and/or epigenetic changes is
preserved.
The proliferation of preneoplastic cells leads to the
formation of benign focal lesions, such as enzyme-altered
foci in the liver, nodules in the mammary gland, polyps in
the colon, papillomas in the skin. Because tumor promo-
ters alter the expression of genetic information without
changing the DNA sequence, tumor promotion is an epi-
genetic process. In addition to causing cell proliferation,
tumor promoters appear to block apoptosis, thus leading
to the accumulation of preneoplastic cells within a tissue.
Some of the lesions that develop due to promotion may
regress, but others acquire additional mutations and prog-
ress to malignant neoplasm. Tumor promotion is a
FIGURE 20.1 The target tissue must be exposed to an initiator first
reversible process up to a certain stage if the promoter is
followed by repeated exposure to promoters in order for the tumors to
withdrawn.
develop. If the time gap between the exposure to initiator and promoter
In order for the tumors to develop, the target tissue varies from a week to a year, tumors will still develop. However, if the
must be exposed to an initiator first and then repeatedly exposure to promoter is first and is followed by exposure to initiator,
exposed to promoters. If the time gap between the tumors will not develop. Also, if the exposure to promoter is not
repeated and spaced over time, tumors is not likely to develop even if
exposure to initiator and promoter varies from a week
the exposure to promoter occurs after exposure to initiator.
to a year, tumors will still develop. However, if the
exposure to promoter is first and is followed by
exposure to initiator, tumors will not develop. Fig. 20.1 cells. At the cytogenetic level, progression is associated
shows the importance of the sequence of exposure with additional mutations and a karyotypic change
to tumor initiator and tumor promoter in tumor because virtually all tumors are aneuploid (have the
development. Table 20.4 shows some common tumor wrong number of chromosomes). Additionally, chromo-
promoters. somal abnormalities, such as deletion, duplication,
or translocation of chromosomal fragments are hallmarks
of tumor progression. Additional mutations in the
Tumor Progression Is a Genetic Process That oncogenes and tumor suppressor genes also accumulate
Involves Transformation of a Benign Tumor during this phase. Because tumor progression is a genetic
Into a Malignant Tumor and Metastasis process that involves the accumulation of additional
of the Malignant Neoplasm mutations (beyond the initiating mutation), tumor initia-
The term tumor progression, coined by Leslie Foulds, tors can also cause tumor progression (Qin et al., 2000;
refers to the stepwise transformation of a benign tumor Becker et al., 2003).
into a malignant tumor and involves autonomous growth Karyotypic instability and accumulation of additional
and metastasis of the malignant neoplasm. Irigaray mutations reflect an ongoing selection of cells suitable for
and Belpomme (2010) defined tumor progressors as carci- neoplastic growth and metastasis (Okey et al., 1998).
nogens that advance mutated cells from promotion to pro- Such increased fitness of a subset of cells for neoplastic
gression, i.e., that allow premalignant mutated cells growth and metastasis is thought to be conferred by
to irreversibly acquire the phenotype of fully malignant specific mutation(s) called driver mutations. The rest of