Page 24 - Color Atlas Of Pathophysiology (S Silbernagl Et Al, Thieme 2000)

P. 24

Development of Tumor Cells
Cell division (mitosis) is normally precisely – growth factors that are formed by tumor
adapted, via local release of growth factors, to cells and autocrinely stimulate their own
meet the specific requirement of cells (→ p. 4). cell division (e.g., Sis, a fragment of the
The growth factors (GFs) stimulate receptors in PDGF)
the cell membranes, which either themselves – receptors for thyroid hormones (ErbA)
show tyrosine kinase activity or stimulate it – receptors for growth factors (e.g., ErbB for
(→ A1). Through the mediation of adaptor pro- EGF and Fms for monocyte-colony–stimu-
teins (GRB 2 ), the GDP/GTP exchange factor SOS lating factor)
binds to certain phosphotyrosine residues and – tyrosine kinases (e.g., Abl, Src, Fes)
then activates the small G protein Ras. The lat- – small G proteins (Ras)
ter, via serine/threonine kinase Raf (→ A2), – serine/threonine kinases (e.g., Raf, Mos)
stimulates a cascade of kinases (mitogen-acti- – transcription factors
vated protein kinase cascade [MAPK cascade]), (Fos, Jun, Myc, Myb, Rel)
and thus leads to the activation of transcrip- As an example, inactivation of Ras is acceler-
tion factors which induce the expression of
ated by a GTPase-activating protein (GAP)
Fundamentals genes essential for cell division. Transcription (→ B). Certain mutations of Ras cancel its sen-
factors which are important for cell division
sitivity to GAP, and Ras remains active.
include Fos, Jun, Myc, Myb, Rel, E2F and DP1.
However, mutations may also produce de-
fective proliferation-inhibiting proteins. Thus,
Thyroid hormones bind to nuclear receptors
division (→ A5). Furthermore, a defect of p53
then similarly promotes gene expression and
1 (ErbA; → A3), the hormone–receptor complex a loss of Rb or p53 promotes uncontrolled cell
cell division. inhibits apoptosis (→ p.13 A).
Mechanisms that promote proliferation are Mutations (→ A, left) can be triggered by
countered by growth-inhibiting factors that chemical cancerogens or radiation, whereby
normally stop excess cell division. They be- disorders of DNA repair favor the occurrence of
come effective, for example, when the cell con- mutations. The cells are especially sensitive to
tains damaged DNA and cell division would mutations during mitosis, i.e., proliferating tis-
lead to defective daughter cells being formed. sues are more frequently subject to mutation
An example of a growth-inhibiting factor is than fully differentiated tissue. This is particu-
retinoblastoma protein (Rb), which binds to larly true for inflammations and tissue lesions,
transcription factors E2F and DP1, and thus in- as they stimulate cell division. Tumor-favoring
activates them (→ A4). For its part Rb is kept mutations can also be inherited. Lastly, viruses
inactivated by the complex consisting of cyclin can bring oncogenes into the host cells (→ A6,
E and the kinase CDK 2 (= E-CDK 2 ) as well as the B1), or can encourage malignant degeneration
complex of cyclin D and the kinase CDK 4 (= D- by inactivation (Rb, p53) or activation (e.g.
CDK 4 ). In this way E-CDK 2 and D-CDK 4 pro- Bcl2) of host-specific proteins.
mote cell division, but their effect is canceled A single mutation is not sufficient for the
by the p21-protein that is expressed under development of a tumor; several mutations
the influence of transcription factor p53. The must occur (→ C2) before the cell is trans-
latter therefore inhibits cell division (→ A4). formed into a tumor cell. Tumor promoters
Oncogenes can arise through mutations of (e.g., phorbol esters; → p. 6) promote the repli-
proliferation-relevant genes. Oncoproteins, the cation of mutated cells and thus the develop-
products of oncogenes, are active even without ment of tumors, without themselves causing
physiological stimulators and can thus trigger mutations (→ C3).
mitosis independent of physiological growth
factors. Examples of oncoproteins (→ A; violet
boxes) are:
14

19 20 21 22 23 24 25 26 27 28 29