world cancer report - iarc

A Injection into transformed cell
B
Phase-contrast micrographs
Fig. 3.31 Selective gap junctional communication: cells transformed by a chemical carcinogen (spindleshaped
and criss-crossed) communicate among themselves, but not with their surrounding non-transformed
counterparts. When a gap junction-diffusible fluorescent dye is microinjected into a single cell
(marked with star) of a transformed focus there is communication between transformed cells but not with
the surrounding non-transformed cells (A, B). Injection of the dye into a non-transformed cell which is
located near a transformed focus results in communication between non-transformed cells, but not with
transformed cells (C, D).
110 Mechanisms of tumour development
Fluorescence micrographs
C Injection into non-transformed cell
D
Transfected cells
carrying the HSV-tk gene
Tumour cell population
Cells carrying the tk gene are
killed by the toxic phosphorylated
GCV (GCV-P) they produce
GCV-P
GCV-P
Ganciclovir
(GCV)
junctional intercellular communication
during carcinogenesis and tumour progression.
Another line of evidence, that implies a
causal role for blockage of intercellular
communication in carcinogenesis, is that
agents or genes involved in carcinogenesis
have been shown to modulate gap junctional
intercellular communication. The
mouse skin tumour-promoting agent 12-Otetradecanoylphorbol
13-acetate (TPA)
inhibits gap junctional intercellular communication.
Many other tumour-promoting
agents inhibit gap junctional intercellular
communication [9]. In addition to such
chemicals, other tumour-promoting stimuli,
such as partial hepatectomy and skin
wounding, have been demonstrated to
inhibit gap junctional intercellular communication.
Activation of various oncogenes,
including those which encode src, SV-40 T
antigen, c-erbB2/neu, raf, fps and ras, also
results in inhibition of gap junctional intercellular
communication. Conversely, some
chemopreventive agents enhance gap junctional
intercellular communication [10].
No bystander
effect
Bystander
effect
GCV-P cannot pass through
the cell membrane
Movement of GVC-P
from cytoplasm to
cytoplasm in gap
junctions
Fig. 3.32 Role of cell-cell interaction in gene therapy. In a tumour cell population, only a few cells can be reached by vectors carrying the HSV-tk gene.
Expression of the tk gene (orange) makes these cells sensitive to ganciclovir: they produce phosphorylated ganciclovir, which is toxic. As phosphorylated ganciclovir
cannot pass through the cell membrane, theoretically only cells expressing the tk gene will die as a result of ganciclovir treatment. Transmembrane diffusion
of phosphorylated ganciclovir from cytoplasm to cytoplasm can induce a bystander effect sufficient to eradicate a tumour cell population, even if only a
few cells express the tk gene [13].