Extracellular growth factors

Extracellular growth factors
The mitotic proliferation of animal cells is initiated
and regulated by a variety of extracellular polypeptide
growth factors, which exert control over individual
cells. These factors stimulate intracellular messengers,
which in turn induce the expression of a set of
primary response genes. Induction is both rapid and
transient: protein synthesis is not required and gene
expression is greatly diminished within a few hours.
The levels of gene products are very low in quiescent
or unstimulated cells; stimulation by various agents
results in a rapid and transient increase in mRNA and
protein. Primary response genes encode proteins that
either activate or repress the transcription of other
genes, resulting in biological responses specifi c to
the stimulating growth factor. The encoded proteins
include members of the Fos and Jun families.
Intercellular communication
Certain cells seem to produce signal molecules which
regulate the growth of cell populations. These putative
molecules are transmitted to neighbouring cells
G2
G1
M
S
Fig. 3.36 The cell cycle. See text for explanation of phases. The enlarging
circles represent an idealized proliferative cell growing to an optimum size
for cell division.
Background physiology and functional anatomy 63
by diffusion through gap junction channels and
never leave the intercellular space. Many studies have
shown that intercellular communication is necessary
for normal growth regulation and that cell proliferation
occurs when intercellular communication
is decreased. Inhibiting the gap-junctional fl ow of
growth-controlling factors leads to neoplastic transformation
of cells and the formation of cancerous
tumours. The specifi c implication of intercellular
communication in growth control has been demonstrated
by experiments in which an exogenous gene
for the gap junctional protein connexin43 was incorporated
into communication-defi cient cancer cells in
culture. Expression of that gene led to the formation
of functional gap junctions and concomitant increase
in intercellular communication, and to inhibition of
growth of these cancer cells (Mehta et al., 1991). Furthermore,
injection of exogenous connexin-expressing
cells into mice suppressed tumour formation
(Rose et al., 1993).
Lowenstein’s group (Mehta et al., 1986) reported
that the growth of cultured cancer cells was arrested
when they were in contact with normal cells. This
growth inhibition was dependent on the presence of
gap junctional communication between the two types
of cell. This fi nding supports the hypothesis that the
gap junctional channels transmit growth-regulating
molecules and that blocking of these channels causes
deregulation. The results are compatible with such
molecules being either inhibitory or stimulatory
signals. The authors suggested two models to accommodate
these alternatives.
In the model operating with inhibitory signals, the
normal (growth-arrested) cell population is the signal
source. The growth-inhibiting signals are transmitted
via the gap junctions to adjacent cancer cells, and from
there are disseminated by the junctional channels
throughout the cancer cell population. In the model
operating with stimulatory signals, the cancer cells are
the signal source. Transmittance of stimulatory signal
to the normal cells reduces the concentration of signal
at source to below threshold level with the result that
the cancerous cells are no longer stimulated to grow
by an excess of their own signals. In either model the
crucial link in the growth inhibition of cancer cells is
the gap junctional communication between the cancer
cells and normal cells.
3.9.3 Apoptosis
Apoptosis is a genetically controlled process of cell
death. Regulation of cell death is essential for normal
development and is an important defence against
viral infection and the emergence of cancer. Excessive
cell death can lead to impaired development and
degenerative diseases, whereas too little cell death can
lead to cancer and persistent and sustained viral infection.
The process of apoptosis is controlled through
the expression of specifi c genes. Some gene products
are activators of apoptosis, whereas others are inhibitors.
NGFI-B, among other primary response gene
products, is an essential mediator of apoptosis (Liu et
al., 1994; Woronicz et al., 1994).
3.9.4 Cancer
Cancer is the result of unregulated cell proliferation
and manifests as malignant tumours, which are either
haematological or solid. Cancer cells have the property
of no longer recognizing appropriate territorial
behaviour and relationships with neighbouring cells.
Cancer can result from the activation of proto-oncogenes
to oncogenes (cancer genes), whose altered
protein products cannot be properly controlled by
the cell. Activation can be induced by point mutations
(altered triplet codon) and frameshift mutations
(insertions or deletions of a single nucleotide or a
segment of DNA); a proto-oncogene can fuse with
another cellular gene; and a normal proto-oncogene
product can be over-expressed. One common feature
of oncogenes is their dominance: only one of the two
copies needs to be altered to induce tumour formation.
Furthermore, the biochemical activity of the
oncoprotein is usually more active than the normal
gene product. Examples of proto-oncogenes are c-jun
and c-fos, whose protein products are components of
the dimeric transcription factor AP-1.
Cancer can also result from inactivation of tumour
suppression genes, allowing the unconstrained
growth of the cancer cell. Deletions or elimination of
the gene itself occur frequently among tumour suppression
genes. These genes are recessive and both
copies must become defective for tumour formation
to occur. Tumour suppression genes are responsible
for many, if not all, of the inherited cancer syndromes.
64 Vitamins: their role in the human body
Examples of this class of genes are p53, which induces
apoptosis, and rb-1, which regulates the cell cycle.
The induction of cancer by chemicals can be divided
into three stages: initiation, promotion and
progression. Initiation refers to the damage to DNA
by a chemical or its metabolite in a linear, dose-related
manner that does not possess a clearly defi ned threshold.
Proliferation of initiated cells allows the genetic
damage to be passed on to daughter cells, after which
event initiation becomes irreversible. Promotion involves
the induction of proliferation of initiated cells
that allows for the ‘locking in’ of the initiation damage
as well as facilitating an environment for further
mutational events in the preneoplastic initiated cells.
Promotion is dose-dependent, exhibits a threshold
and is reversible. The third stage, progression, is the
least defi ned and involves the irreversible transition
from preneoplastic to neoplastic cells. The combined
sequence of events is referred to as neoplastic transformation.
Chemical carcinogens may be either genotoxic or
nongenotoxic: both stimulate DNA synthesis and cell
proliferation in target tissues. Genotoxic compounds
function in the initiation stage of cancer; they damage
nuclear DNA through mutation and chromosome
changes. The mode of action of nongenotoxic
carcinogens has not been established, but they are
capable of inhibiting intercellular communication.
Tumour-promoting phorbol esters are nongenotoxic
compounds which bind to and activate protein kinase
C, apparently by substituting for diacylglycerol as an
activator of this enzyme. One common cellular effect
of phorbol esters and other nongenotoxic carcinogens
is the inhibition of intercellular communication
through gap junctions.