From ScienceWeek scienceweek.com
(5 Jan '01 issue)
6. MEDICAL BIOLOGY: ORIGINS OF CANCER
In general, cancer involves a loss of normal cellular growth
control, the loss of control producing a growing tissue mass
called a "tumor" or "neoplasm". Uncontrolled growth occurs not
because the replication rate of cancer cells is always greater
than the replication rate of normal cells, but because of the
difference between the replication rate of cancer cells and the
rate of loss of cancer cells. In normal tissue, a precise balance
between replication rate and rate of loss is maintained; in a
growing neoplasm, this balance is absent and the replication rate
exceeds the rate of loss.
... ... Daniel Haber (Massachusetts General Hospital, US)
presents a review of the etiology of breast cancer, the author
making the following points concerning the origins of cancer ingeneral:
1) The author points out that cancer results from the
accumulation of mutations in genes that regulate cellular
proliferation. These mutations can occur early in the process of
malignant transformation or later, during progression to an
invasive carcinoma. The earliest mutations occur in the *germ
line, as in the case of cancer-prone families. In these
instances, the inheritance of a mutated *allele is commonly
followed by the loss of the second allele from a somatic cell,
leading to the inactivation of a tumor-suppressor gene and
triggering malignant transformation. A classic example is
hereditary retinoblastoma, in which there is inheritance of a
mutant germ-line _RBI_ allele (a *tumor-suppressor gene) followed
by somatic mutation of the normal _RBI_ allele.
2) Genes important to the development of cancer regulate
diverse cellular pathways, including the progression of cells
through the *cell cycle, resistance to programmed cell death
(apoptosis), and the response to signals that direct *cellular
differentiation. Moreover, the inactivation of genes that
contribute to the stability of the genome itself can favor the
acquisition of errors in other genes that regulate proliferation.
3) Errors in DNA that arise during normal replication of the
molecule (nucleotide mismatches), or that are induced by ionizing
radiation or genotoxic drugs, can cause mutations in coding
sequences or breaks in double-stranded chromosomal DNA. If the
nucleotide mismatch is not repaired before a round of DNA
replication occurs, that mutation is transmitted to daughter
cells. An unrepaired break in double-stranded DNA can cause a
mitotic catastrophe when the cell attempts to segregate broken
chromosomes. Studies of yeast have identified genes that sense
damaged DNA and cause the arrest of the cell cycle, which allows
time for the molecular defect to be repaired. These genes operate
at several specific "checkpoints" in the cell cycle as a means of
ensuring genomic integrity before DNA is synthesized.
4) The most critical checkpoint gene yet identified that is
related to cancer in humans is the tumor suppressor gene _p53_.
This gene is not essential for cell viability, but it is critical
for monitoring damage to DNA. Inactivation of _p53_ is an early
step in the development of many kinds of tumors. In cases of
cancer without _p53_ mutations, there are frequently alterations
in two other genes (_MDM2_ and _p14_) that regulate theexpression of _p53_.
-----------Daniel Haber: Roads leading to breast cancer.
(New England J. Med. 23 Nov 00 343:1566)
QY: Daniel Haber: Massachusetts General Hospital, Boston, MA02114 US.-----------
Text Notes:... ... *germ line: A germ cell is any cell from which gametes
(sperm cells and egg cells) are derived. All other cells are
called "somatic" cells. In general, the term "germ line" refers
to the line of differentiated germ cells.
... ... *allele: An allele is one of two or more forms of a
given gene that control a particular characteristic, with the
alternative forms occupying corresponding loci on homologouschromosomes.
... ... *tumor-suppressor gene: In general, cancer genes have
been divided into 2 classes, proto-oncogenes and tumor suppressor
genes. Proto-oncogenes are genes that sustain activating changes
in human cancer. These changes may take the form of point
mutations or gene rearrangements that lead to increased or
uncontrolled activity of the encoded protein, or they make take
the form of gene amplification, which results in increased levels
of protein expression. In contrast, tumor suppressor genes are
characterized by inactivating changes in human cancer, typically
point mutations that result in truncation or functional
inactivation of the encoded protein, or gross deletions of
chromosomal fragments carrying these genes.
... ... *cell cycle: In this context, the term "cell cycle"
refers to the entire life history of a single cell from mitosis
to mitosis, including the sequence of intervening phases.
... ... *cellular differentiation: In general, in this context,
the term "differentiation" refers to the structural and
functional specialization of cells, developmental cell
specialization (morphology and biochemistry) resulting from
activation of specific parts of the cell genome.-------------------
Summary & Notes by SCIENCE-WEEK scienceweek.com 5Jan01
For more information: scienceweek.com
Related Background:MEDICAL BIOLOGY: ON MUTATIONS AND CANCER
The term "cancer", which means "crab" in Latin, was introduced by
Hippocrates (460-370 B.C.) to describe diseases in which tissues
grow and spread unrestrained throughout the body, eventually
causing death. Cancers can originate in almost any tissue of the
body, including nerve, muscle, blood, connective tissue, etc.
Depending on the cell type involved, cancers are grouped into 3
main categories: a) carcinomas, the most common types of cancer,
arise from the *epithelial cells that cover external and internal
body surfaces, with lung, breast, and colon cancers the most
frequent cancers of this type; b) sarcomas originate in
supporting tissues of *mesodermal origin, such as bone,
cartilage, fat, connective tissue, and muscle; c) lymphomas and
leukemias arise from cells of blood and *lymphatic origin, the
term "leukemia" used when such cancer cells circulate in large
numbers in the bloodstream rather than growing mainly as solid
masses of tissue. Cancer is a disease of the genomic apparatus of
the cell, in particular of the growth-regulation apparatus, and
considering the vast number of activities that must be
coordinated and regulated by the genomic apparatus during the
lifetime of each cell, it is not surprising that malfunctions
arise. In general, cancer is the most prominent of the many
diseases arising from aberrations in cell function, with more
than 25 percent of people in the US now expected to develop
cancer in their lifetime.
... ... C.R. Boland and L. Ricciardiello (2 installations, US)
present a review of current research on the genomic basis of
cancer, the authors making the following points:
1) It has been known during most of this century that cancer
is often associated with visible derangements in the nucleus of
the cell. The cells of solid tumors commonly exhibit chromosome
duplications, deletions, and rearrangements, but before the
organization of the human cell nucleus was understood, these
chromosome aberrations were difficult to categorize and were of
little help in understanding the biological basis of cancer.
2) Within a few decades after the discovery of the structure
of DNA, cancer-related genes (oncogenes) were isolated, and these
were frequently found to be mutant versions of normal cellular
genes in which an activating *point mutation or an aberrant
*genetic amplification process resulted in a gain of function for
that gene product, and a growth advantage for that aberrant cell.
But as more and more oncogenes were identified, researchers
realized that tumor growth was also associated with loss of
function of certain "tumor suppressor genes". These tumor
suppressor genes were often inactivated by their deletion from
the nucleus, and the phrase "loss of heterozygosity" (LOH) was
applied to genetic loci in which both *alleles were present in
normal tissues, but one copy was lost in tumor tissue. In many
instances, tumor suppressor genes were first identified by virtue
of germ-line mutations that were present at a high frequency in a
rare tumor, e.g., retinoblastoma, but it soon became apparent to
researchers that many tumor suppressor genes were associated with
a variety of different tumors, many of which were not rare atall.
3) There are no oncogenes or tumor suppressor genes that are
activated or deleted in and from all cancers. Even tumors of a
single organ rarely have uniform genetic alterations, although
tumor types from one specific organ do have a tendency to share
mutations in certain genes or in different genes within a single
growth-regulatory pathway.
4) At the present time, it is not known how many critical
mutations are required to convert a single normal cell into a
malignant cell. Human cells have been difficult to transform in
vitro, and the basis for this difficulty is not yet understood.
The simplest model of tumorigenesis is as follows:
... ... a) Human cells experience a certain number of mutations
each day as a result of exposure to carcinogens or as a result of
ordinary biological degradation, both of which can alter
nucleotide sequences. Errors will also occur during new DNA
synthesis and in the process of disentangling the chromosomes
during *mitosis. Most of these errors would be either irrelevant
to the life of the cell or deleterious because of the loss of a
gene critical for cellular viability.
... ... b) By chance, an occasional genomic mutation might create
a growth advantage for a cell, permitting increased net cellular
growth, because of increased proliferation or a reduction in
programmed cell death (reduction in apoptosis), with a resulting
*clonal expansion of that lineage. A second genomic alteration
might then occur within this expanding clone, again by chance,
providing an additional growth advantage for that cell and its
progeny. By virtue of these two advantages, the cells of this
clone would eventually overgrow neighboring cells, creating yet
another expanding clone. This scenario would repeat as a
consequence of each new mutation that provided an additional
growth advantage. The accumulation of these growth promoting
mutations is the basis of the current view of "multistepcarcinogenesis".
-----------C.R. Boland and L. Ricciardiello: How many mutations does it take
to make a tumor?(Proc. Natl. Acad. Sci. US 21 Dec 99 96:14675)
QY: C. Richard Boland [crboland@ucsd.edu]-----------Text Notes:
... ... *epithelial cells: In animals, "epithelial cells"
compose the cell layers that form the interface between a tissue
and the external environment, for example, the cells of the skin,
the lining of the intestinal tract, and the lung airway passages.
... ... *mesodermal: In the embryos of higher animals, there
occurs the transformation of a single-layer "blastula" into a
3-layered "gastrula" consisting of ectoderm (outermost layer),
mesoderm (middle layer), and endoderm (innermost layer)
surrounding a cavity with one opening. The 3 layers are called
the "germ layer", and these layers, via further cell
differentiation and proliferation, determine the development of
all the major body systems and organs.
... ... *lymphatic: The lymphatic system is a complex network
for the distribution of lymph fluid (which is similar to blood
plasma -- blood without red cells). Lymph is collected by
drainage from the tissues throughout the body, flows in the
lymphatic vessels through the lymph nodes, and is eventually
added to the venous blood circulation.
... ... *point mutation: A minor changes in the genome; a single
base-pair substitution.
... ... *genetic amplification process: The production, by
various means, of additional copies of a stretch of genomic DNA.
... ... *alleles: One of two or more forms of a given gene that
control a particular characteristic, with the alternative forms
occupying corresponding loci on homologous chromosomes.
... ... *mitosis: Programmed division of the nucleus during cellreplication.
... ... *clonal expansion: This refers to the expansion of a
population of cells all derived from repeated replications of
progeny of a single cell.-------------------
Summary & Notes by SCIENCE-WEEK scienceweek.com 14Jan00
For more information: scienceweek.com]-------------------
Related Background:ON GENETICS AND HUMAN CANCERS
The current consensus is that cancer results from the
accumulation of mutations in the genes that directly control the
birth and death of biological cells. But the mechanisms through
which these mutations are generated are the subject of continuing
debate and much research. It has been argued that an underlying
genetic instability is absolutely essential for the generation of
the multiple mutations that underlie cancer. On the other hand,
it has also been suggested that normal rates of mutation, coupled
with waves of *clonal expansion, are sufficient for the cancer
process to occur in humans. ... ... C. Lengauer et al (Johns
Hopkins University, US) present a review of observations
concerning the stability of the genome of human cancer cells, the
authors making the following points:
... 1) Numerous genetic alterations that affect growth-
controlling genes have been identified in neoplastic cells over
the past 15 years, and these observations provide persuasive
evidence for the genetic basis of human cancer. The alterations
can be divided into 4 major categories:
... ... a) Subtle sequence changes: These changes involve
nucleotide base substitutions or deletions or insertions of a few
nucleotides in the genome, and unlike the alterations described
below, they cannot be detected via cytogenetic analysis. Such
mutations, for example, occur in over 80 percent of pancreaticcancers.
... ... b) Alterations in chromosome number: Such alterations
involve losses or gains of whole chromosomes. Such changes are
found in nearly all major human tumor types.
... ... c) Chromosome translocations: These alterations can be
detected cytogenetically as fusions of different chromosomes or
of normally non-contiguous segments of a single chromosome. At
the molecular level, such translocations produce fusions between
two different genes, endowing the fused genetic entity with
tumorigenic properties. Such translocations are known to occur in
the *chronic myelogenous leukemias.
... ... d) Gene amplifications: These are seen at the cytogenetic
level as homogeneously stained regions, and at the molecular
level they involve multiple copies of a gene. An example of gene
amplification occurs in advanced *neuroblastomas.
... 2) All 4 of the alterations described above occur commonly in
specific tumor types but are rarely or never observed in normal
cells. However, the existence of genetic alterations in a tumor,
even when frequent, does not mean that the tumor is genetically
unstable. By definition, instability is a matter of rate, and the
existence of a mutation provides no information about the rate of
its occurrence. The higher prevalence of mutations in tumor cells
compared with normal cells still requires explanation.
... The authors conclude: "One can argue persuasively that all
chemotherapeutic compounds used at present are more toxic to
cancer cells than to normal cells only and specifically because
of the defective *checkpoints that occur in cancer cells. This
line of reasoning suggests that, although instability may be
essential for neoplasia to develop, it may also prove to be its
Achilles' heel when the tumor is attacked by the right agents.
Further research to define the molecular and physiological bases
of instability may, therefore, yield entirely new approaches to
treating common forms of cancer."-----------
C. Lengauer et al: Genetic instabilities in human cancers.
(Nature 17 Dec 98 396:643)QY: Christoph Lengauer: lengauer@jhmi.edu-----------
Text Notes:... ... *clonal expansion: In this context, this refers to the
expansion of a population of cells all deriving from a singlemutated cell.
... ... *chronic myelogenous leukemias: (granulocytic leukemias)
These leukemias are characterized by an uncontrolled
proliferation of myelopoietic cells (blood cells derived frombone marrow).
... ... *neuroblastomas: Neuroblastomas are malignant neoplasms
characterized by only slightly differentiated immature nerve
cells of embryonic type.
... ... *checkpoints: In this context, the term "checkpoint"
refers to a point in the eukaryotic cell division cycle where the
cycle can be halted until conditions are suitable for the cell to
proceed to the next stage. (eukaryotic = containing membrane-
bound organelles such as a nucleus.)-------------------
Summary & Notes by SCIENCE-WEEK scienceweek.com 26Mar99
-------------------Related Background:
ANEUPLOIDY AND GENETIC INSTABILITY OF CANCER CELLS
In general, germ cells (egg cells and sperm cells) and somatic
cells (non-germ cells) carry different numbers of chromosomes,
with germ cells carrying exactly half the number (haploid number)
of somatic cell chromosomes (diploid number). The term
"aneuploidy" (heteroploidy) refers to a condition in which the
number of chromosomes in a cell is not an integer multiple of the
haploid number typical for that cell or organism. For example,
the haploid human chromosome number is 23; the normal somatic
cell contains 46 chromosomes; a somatic cell with 47 or 44
chromosomes is aneuploid. Some authors, however, use the term
"aneuploidy" to indicate merely an abnormal number of
chromosomes. In cell biology, the term "karyotype" refers to the
characteristics profile (number, size, and shape) of a set of
chromosomes of a cell or organism. In this context, the term
"phenotype" refers to the total appearance of a cell as
determined by the interaction during development between its
genetic constitution (genotype) and the cell's environment.
Genetic and phenotypic instability are hallmarks of cancer cells,
but the cause of the instability is not clear. The leading
hypothesis suggests that a poorly defined gene mutation generates
genetic instability and that one or more of the many subsequent
mutations then cause cancer [*Note #1]. ... ... P. Duesberg et al
(2 installations, DE US) report an investigation of the
hypothesis that genetic instability of cancer cells is caused by
aneuploidy, which they define as "an abnormal balance of
chromosomes". The authors point out that because symmetrical
segregation of chromosomes during mitosis depends on exactly two
copies of the genes involved in mitosis ("mitosis genes"),
aneuploidy involving chromosomes bearing mitosis genes will
destabilize the karyotype. The authors propose that the
aneuploidy hypothesis predicts that the degree of genetic
instability should be proportional to the degree of aneuploidy,
and it should thus be difficult to maintain the particular
karyotype of a highly aneuploid cancer cell on *clonal
propagation. The authors report this prediction is confirmed with
clonal cultures of chemically transformed aneuploid Chinese
hamster embryo cells. Defining the "ploidy factor" as the
quotient of the modal chromosome number divided by the normal
number of the species, it was found that the higher the ploidy
factor of a clone, the more unstable was its karyotype. The
authors point out that work by others has established an exact
correspondence between the karyotype instability of human colon
cancer cell lines and the degree of aneuploidy. The present
authors suggest that, independent of gene mutation, aneuploidy is
sufficient to explain genetic instability and the resulting
karyotypic and phenotypic heterogeneity of cancer cells. The
authors further suggest that because aneuploidy has also been
proposed to cause cancer, their hypothesis "offers a common,
unique mechanism of altering and simultaneously destabilizing
normal cellular phenotypes."-----------
P. Duesberg et al: Genetic instability of cancer cells is
proportional to their degree of aneuploidy.
(Proc. Natl. Acad. Sci. US 10 Nov 98 95:13692)
QY: Peter Duesberg: duesberg@uclink4.berkeley.edu-----------Text Notes:
... ... *Note #1: In 1976, Peter Nowell postulated that a
precancerous mutation generates exceptional "genetic instability"
or "mutability", and that the highly mutable "premalignant" cell
then suffers many further gene mutations, including those that
cause cancer (P.C. Nowell, Science 194:21 1976).
... ... *clonal propagation: In general, in this context, a
"clone" is a line of identical cells produced from one or a few
originating cells.-------------------
Summary & Notes by SCIENCE-WEEK scienceweek.com 22Jan99
For more information: scienceweek.com
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