Cancer, from an Embryological Point of View

Let's begin with some medical history:

Within living memory, tuberculosis used to be nearly incurable,
killed more Americans per year than cancer, and had the same
reputation as cancer for inexorable killing. Tuberculosis was what killed
Anton Chekhov, Robert Louis Stevenson, the mathematician Riemann, all
4 Brontes, Chopin, Emerson, Kafka, Keats, D.H. Lawrence, Thoreau,
Thomas Wolfe, George Orwell and two of President Richard Nixon's brothers,
most around age 40. A diagnosis of tuberculosis used to be an inexorable
death sentence
, but this disease then became almost completely curable
with the drugs streptomycin and isoniazid.

I wish I didn't have to admit that resistant strains of tuberculosis have
developed, and have killed millions in poor countries. Nevertheless, the
key points are (first) that breakthroughs do occur, and (second) that medical
breakthroughs are usually based on clever ideas, pursued ruthlessly.

Both for Waksman's discovery of streptomycin in the United States, and
Fleming's discovery of penicillin in Britain, the clever idea was that
micro-organisms might make highly selective poisons that fight germs.

In the search for more antibiotics to fight germs, many chemicals were
discovered that kill cancer cells. None of these have the specificity of
penicillin; they all hurt normal non-cancerous cells but not quite as much
as they hurt cancer cells.

Specificity is the problem: How to find poisons that are specifically poisonous
for germs, or for cancer cells. Specificity always depends on some a
difference between animal cells and bacteria; or a difference between
normal body cells and cancer cells. Any sort of difference can work.

Penicillin gets its specificity from bacterial cell walls; It forms covalent
bonds with the active sites of the enzymes that build bacterial cells walls,
allowing osmotic pressure to burst the bacteria. Animal cells don't have
cell walls, so they aren't harmed.

Streptomycin gets its specificity from differences between procaryotic and
eucaryotic ribosomes. The procaryotic type of ribosomes are distorted more
that the eucaryotic kind.

There are entire books listing selective poisons, and the reasons why they
harm one organism more than others. In every case, the reason is some
difference in the biochemistry, or the physical properties, or their
permeability, or something. An excellent book titled "Selective Toxicity"
lists list hundreds or maybe thousands of specific examples of poisons
that hurt or kill some organisms, but not others. This specificity is always
based on a difference; and based on this book, I think absolutely any
difference can be exploited to create a selective poison.

Fortunately, there are at least a dozen consistent differences between cancer
cells and equivalent normal cells. That implies that two dozen fundamentally
different kinds of anticancer drugs ought to be possible, each based on
exploiting one of the differences, and selectively killing just those cells
that have the difference found in cancer cells.

Unfortunately, almost all the effort has been put into treatments that
interfere with DNA synthesis and mitosis. Not that this effort hasn't
been extremely successfully. Dozens of chemotherapy drugs have been
synthesized or isolated from plants, animals and microorganisms, almost
all of which interfere with cell growth. These have been very successful
in curing the fastest growing kinds of cancer, such as childhood leukemia
and Hodgkin's Disease. Most of the side effects of these drugs also affect
faster-growing normal cells. They produce anemia by harming fast growing
cells in bone marrow; they cause hair loss by harming growing hair cells;
and they produce nausea.

People with slower-growing cancers are less often cured.

Here are some other abnormalities of cancer cells, each of which might be
turned into a new kind of therapy. All you need to do is invent chemicals,
or other treatments, that selectively kill those cells that have one or more
of these abnormal properties.

1) Glucose uptake is much higher than normal in most cancer cells.
Related to this is an abnormally (very) large secretion of lactic acid,
and abnormally low amounts of ATP production by mitochondria. This set of
inter-related abnormalities was discovered around 1930 by Warburg, who had
won the Nobel Prize for previous discoveries, and is one of two (unrelated)
phenomena both called "The Warburg Effect". Excess glucose uptake into cancer
cells is the reason why PET scans can detect cancer, and reliably distinguish
cancer cells from normal cells. I have had several PET scans myself,
and they accurately mapped the tumors. They cost about three thousand
dollars per scan.

The biochemical cause of these phenomena remains unknown, and very little
research has been done on it, because it doesn't fit in with oncogene research.
The best English language textbook on cancer biology doesn't even mention
the Warburg effect. Almost no research has been done about how to kill cancer
cells based on either their anaerobic metabolism, or the excess uptake of
glucose. (Despite very large amounts of research on how to use the phenomenon
to map tumors).

2) MRI images of cancer cells are dramatically different than normal tissues.
This was the subject of the first research paper about MRI.
Nobody ever discovered the reason why cancer cells' MRI images are abnormal.
Almost no research has been done on the subject.

3) The acto-myosin cytoskeleton of cancer cells is disorganized,
and they exert much weaker traction forces as they crawl.

4) Cancer cells can crawl onto less adhesive substrata,
from more adhesive substrata. This is a loss of haptotaxis.

It was discovered by Prof. Barbara Danowski, as part of her PhD research
in this department. She invented the experiment herself. She then did
important research at the University of Pennsylvania, and is now
Professor and Chair of Biology at Union College in New York.
I had never considered the possibility, until she proved it.

5) Defective cell-cycle checkpoint controls.
For example, cancer cells tend to go ahead and copy DNA, even if it is damaged.
Normal cells would delay starting to copy their DNA until
damage to it has been repaired.

6) Excessive inhibition of apoptosis.
In particular, 95% of cases of the "follicular" kind of Non-Hodgkin's lymphoma
are caused by a breakage and incorrect re-joining of the 14th chromosome
and the 18th chromosome, in such a way that the promoter region of the
antibody heavy chain gene is next to a gene named bcl-2. This stands for
b-cell lymphoma two, because it was the second lymphoma-causing gene to be
discovered by looking for chromosome translocations in cancerous lymphocytes
of human patients. Nematodes have a gene almost identical to human bcl-2.
It is needed to inhibit programmed cell death, both in vertebrates and in
nematodes (and probably all animals). Experimenters have even spliced the
human DNA sequence for bcl-2 into nematodes, in place of the nematode's own
gene. The human gene works fine in nematode embryonic development.

When a human b-lymphocyte has this particular chromosome translocation,
it makes bcl-2 protein instead of antibody, and can't undergo programmed
cell death. Although such lymphocytes don't grow or divide any faster than
normal lymphocytes, they do accumulate without limit. Eventually, they
displace your normal lymphocytes and fill up your bone marrow, until you
become anemic, can't make antibodies etc. and die.

Ironically, the treatment is often a chemical designed to kill fast-growing
cells by damaging their DNA. It was assumed the cancerous lymphocytes must
be growing too fast, and that cross-linking their DNA would selectively kill
the fastest growing lymphocytes.(That, itself, isn't very logical.
Why should it kill a cell to prevent it from doing something abnormal?
If they grew slower than normal, would you expect to be able to kill them
by speeding them up?)

Consider the following hypothesis about how chemotherapy really works:
When DNA is damaged by radiation or a drug like cyclophosphamide,
non-cancerous cells detect the damage and slow down their growth,
halting at a check-point until the damaged DNA has been fixed.
The cancerous cells, however, because their check-point controls are broken,
continue to copy DNA and undergo mitosis. This failure to stop is really
what kills them. This is sort of the opposite of what had been assumed.
Cancer cells die because they can't stop, not because they grow too fast.
Any time a drug works, there must be some reason; but the true reason may
be very different than what the drug was designed to do.

7) Lack of anchorage dependence, the ability of cells to survive
and continue dividing without being spread out on a solid substratum.
Cancer cells can grow and survive suspended in a gel. Non-cancerous cells
will undergo programmed cell death if you culture them on an area of substratum
that is smaller that the area they normally occupy when attached to a Petri
dish. Nicholas Maroudas and Donald Ingber have done the best research on this.

8) Increased secretion of proteolytic enzymes(metalloproteases, etc.)

9) Loss of differentiated characteristics ("tumor progression")

10) Gain of abnormal combinations of gene transcription


There are more kinds in addition; nobody even knows how many more there are,
and almost no research or funding goes toward searching for more.


I) The disease cancer results from a cell of your own body
changing so that it and its mitotic daughter cells divide and crawl without limit.

It is normal for body cells to grow and divide, and to crawl from place to place.

But cell growth and cell locomotion are normally controlled, by embryological
mechanisms,which are only partly understood.

"Contact inhibition" means the normal inhibition of cell growth
by crowding, and directional inhibition of cell crawling where
once cell touches another.

Diagrams of the quantitative experimental tissue culture measurements
one by Michael Abercrombie and Joan Heaysman, by which they discovered
and proved the existence of contact inhibition of cell locomotion
By these criteria, they also discovered that cancer cells in
tissue culture have less sensitivity to contact inhibition; that seems likely
to be at least part of the reason for their increased invasiveness.
Other researchers later used the phrase "contact inhibition" to mean
reduced rates of cell growth and mitosis in crowded tissue cultures.

Cancer cells are likewise less inhibited than equivalent normal cells.

For many years, other scientists confused these two uses of the phrase
"contact inhibition" (inhibition of growth as well as locomotion),
assumed the same mechanism caused both, and that cancer cells always lacked
(which Abercrombie never claimed). Then people over-reacted
in the opposite direction. The inhibition of locomotion now seems
to be caused by prevention of actin fiber assembly
near where cells
touch each other. Much more research is needed to find out whether cancer
cellsare more able to continue crawling where they touch other cells,
whether this is related to their uncontrolled growth, or if such
abnormalities can be targeted by new kinds of chemotherapy.

These mechanisms of inhibition of growth and of locomotion
may or may not have the same (or overlapping) mechanisms.

Tissue cells (including body cells in tissue culture) crawl by means
of traction forces exerted behind their leading edges.
Traction forces are exerted mostly behind areas where the plasma membrane
bends, bubbles and fold irregularly in a process called "ruffling"
(as can be seen in the video time lapse sequences below).
These cell surface movements were was once thought to be peristaltic,
but now are now known to be caused by continual re-assembly of cytoplasmic
actin. Part of contact inhibition is the paralysis of ruffling where
two cells touch each other, as shown in the diagram below.

Many tissue cells behave as if actin assembly is somehow turned off where
one cell touches another. Such cells behave as if the mechanism of
locomotion is inhibited next to cell-cell adhesions. Sometimes one or both
cells turns or crawls away from the cell-cell contant; and sometimes new
cell-cell adhesions form, and the adhering parts of both cell margins cease
locomotion and ruffling.

II) The great majority (>95%) of human cancers are caused by
somatic mutations in a few specific genes (called "Oncogenes").

In many other species, large fractions of cancers are caused
by communicable viruses. (Examples include cats and turkeys)

This department gives a very good course specifically about
oncogenes and how they cause cancer.

III) Several sexually transmitted papilloma viruses cause
cervical cancer in women. A vaccine has recently been developed
which inhibits infection by these cancer-causing papilloma viruses.

Many newspapers etc. have confused this with 'a vaccine against cancer.'

An editorial in the News and Observer a few years ago "explained"
that the vaccine "Is not yet approved for boys." but didn't ask "Why not?".

These viruses infect both sexes: but the cancers they cause are in females.

What was their reasoning for vaccinating only one sex?
After all, from whom do females catch these viruses?

IV) Cancer cells retain many of the properties of whichever
differentiated cell type they began from:

 Carcinomaa cancer of some epithelial cell type
 Adenomaa cancer of some glandular cell type
 Sarcomaa cancer of some mesenchymal cell type
 Leukemiacancer of one of the kinds of white blood cells
 Lymphomacancer of lymphocytes, such as those that make antibodies
 Teratomaa cancer of primordial germ cells
a cancer of undifferentiated nerve cell precursors.
(Once nerve cells form axons, they never divide again)

V) Malignant cancers are invasive (loss of control of cell crawling)
Benign tumors are not (yet!) invasive, but may become so.

Metastasis is transfer of cancer cells from one part of the body
to another by breaking free into the lymph or blood (or coelom, or rarely, urine!)

Once cancer cells have begun to metastasize, then it is very
much less possible to remove them all surgically.
(Thus, the great importance of early detection)

[Except for lymphoma, etc. which are metastatic very early]

VI) Diagnosis of cancer cells by shape and behavior

Cancer cells are usually somewhat abnormal in shape and structure,
as seen under the microscope in histological sections.

The well known Pap test depends on this fact, although it
uses tissue scrapings rather than sections. It is not unusual for cancer
operations to begin with the surgeons cutting out a small chunk of the tumor,
then sending it down the hall to the histology lab for quick fixation,
sectioning, staining and examination by a skilled pathologist.
Just by looking at the shapes of the cells and particularly the shapes
of the nuclei, the pathologist is supposed to be able to tell whether the
tissue is malignant or not.

Often there are 3 options: (1) stitch up the incision, because the tissue
is benign; (2) continue with the operation and try to remove as much as possible
of the tumor, because it is malignant, or; (3) stitch up the
incision, because the cells are so extremely malignant that experience
has proven that there is no hope from surgery.

The patient, lying there waiting, and his family members waiting down the
hall, might wonder what cellular differences the pathologist
is looking for.

Books have been written summarizing the criteria used for this purpose.
The quotation below is from "The Cytological Diagnosis of Cancer"
by Ruth M. Graham, 3rd. edition Saunders, Philadelphia.
(Health Sciences Library QZ 241 G 741 1972 ) page 379:

"Whether a cell is malignant or benign is determined by its nucleus;
what type of malignant or benign cell it is determined by the cytoplasm."

"In examining a cell, the microscopist should first look at the nucleus
and decide whether it is benign or malignant."

"The first feature to look for is the orderly arrangement of the
. Are the chromatin particles of equal size? Are they
distributed evenly throughout the entire nucleus? Is the nuclear
border smooth and even in thickness
? Does each part of the nucleus
resemble every other part? If, in the mind's eye, the nucleus were
bisected, would the two halves be mirror images of one another?
If the answers to these questions are "yes", then one
can be sure the nucleus is benign.

On the other hand, if the answers to these questions are "no";
if the chromatin particles differ in size; if they are distributed unequally
at the nuclear border, and in the bisected nucleus no part is a mirror image
of any other part, then one can be sure that the nucleus is malignant. "

Note that these criteria are entirely empirical
(arrived at purely by experience, not based on any theory or other reason
for expecting them). Cells with one set of properties always turned out
to be malignant in their future behavior (if not removed), while cells with
the other sets of properties always turned out to be benign. Mistakes are
sometimes made, even mistakes in the direction of diagnosing malignant cells
as benign; but given the amounts of money involved in malpractice lawsuits,
it seems noteworthy to me that the quotes above could be so general and
sweeping. It is almost as if the weather could be accurately predicted
from the shapes of clouds, but no one had bothered to find out the physical
causation relating the shapes of today's clouds to the occurrence of tomorrow's
storms! There has been little or no research into the question of how
cell and nuclear shape is related to oncogene function.

The histological organization of cancer cells is also abnormal;
the cells' arrangements as "sloppy": they are irregular in shape, sizes and
relative positions, as well as slightly out of alignment
What does this imply about the mechanisms that control cell shape, size,
relative position, alignment, etc.? Would you prefer to say that the
cancerous state interferes with these mechanisms? Or would you say that
malignancy results from the disruption or failure of these mechanisms?
Your new ideas might really help treatment.






VII) How you might invent a new cure for cancer!
Always keep in mind, the key problem is specificity


Initiation of Apoptosis Abnormalities of cancer cells
i) Caspase enzyme activation a) Over-activity of certain kinases
ii) Non-self, viral-like peptides
b) Excessive phosphorylation of certain proteins
(held by type I histocompatibility antigens)
iii) Fas/Fas ligand stimulation c) Mutated GTPases, unable to hydrolyse GTP
iv) Other damage to cells?
d) Anaerobic metabolism
e) Inability to halt at cycle checkpoints
f) Lactic acid production
g) Secretion of proteolytic enzymes
h) Disrupted cytoplasmic actin
i) Abnormal adhesions
j) Less fibronectin secretion

VIII) Examples of Current Methods of Cancer Chemotherapy:

"Nitrogen mustards" such as cyclophosphamide
(chemical relatives of "mustard" war gasses used in World War I)
damage DNA, and tend to kill faster-growing cells.

"Spindle poisons" such as vinblastine, which bind selectively
to tubulin and block formation of the mitotic spindle.

Monoclonal antibodies, with binding sites that specifically fit cell surface
proteins that happen to be more numerous on a given patient's cancer cells.
For example "Herceptin"
Or that attack all the patient's cells of the same differentiated cell type
as that person's cancer. For example, "Rituxan" attacks ALL of a person's

Monoclonal antibodies can also be made that are specific for an individual
person's B-cell lymphoma but they are regarded as "prohibitively expensive"
and are not being widely used. See this quote
from a widely used immunology textbook

Notice the lack of specificity of any of these categories of treatments.
None of them is even designed to kill only cancer cells.

Also notice that monoclonal antibodies aren't really drugs, but are medically
equivalent to the passive immunity of anti-snake bite injections.
They were invented by British government researchers in Cambridge, England.

More hopeful developments: A researcher synthesized a chemical that
selectively blocks a certain ATPase protein made only by lymphoma cells
of a certain sub-type. This is a "fusion protein" coded for by DNA sequences
that were originally on different chromosomes, but two
chromosomes often break and rejoin at the wrong places, creating the
"Philadelphia Chromosome", and coding for an over-active kinase that
stimulates cell growth and inhibits apoptosis.
The synthetic chemical drug (called Gleevec) has enough specificity for this
fusion protein enzyme to kill 99% + of many patients' cancerous lymphocytes.

There were many optimistic news reports about this drug in the past few years.
Nevertheless, I think you and I should be more curious about

#1 Why it kills cells to block activity of this abnormal enzyme?
(that they aren't supposed to have, anyway!)

#2 Considering that cells have about a thousand normal ATPases,
what are some possible reasons why a poison can inhibit only one?

Possible explanations are (1) maybe this abnormal enzyme is keeping cells
from killing themselves by apoptosis, so weakening it lets them die;
and (2) maybe the inhibitor also inhibits many or all of the other, normal
ATPases, but that doesn't hurt normal cells unless their apoptotic machinery
were already activated.

But #3, these paradoxical aspects were never mentioned in news stories.

Like almost everyone else, I expected that when the causes of cancer
were completely understood at the molecular level then we would see how to cure it.

So far, however, this information (about oncogenes, etc.) has not been useful
for curing patients. What is needed are methods to kill just
those cells in which oncogenes are over-active.

Blocking the activity of oncogenes doesn't really do you any good.
You have to kill just those cells in which the oncogenes are causing cancer.

That is so important to remember; let me repeat that:

You have to kill just those cells in which the oncogenes are causing cancer.
You have to kill just those cells in which the oncogenes are causing cancer.
You have to kill just those cells in which the oncogenes are causing cancer.
You have to kill just those cells in which the oncogenes are causing cancer.

You have to kill just those cells in which...    don't forget.


IX) Some specific examples of oncogenes.
(About which you can learn much more in this department's course "The Biology of Cancer")

sis: Codes for a form of PDGF (Platelet Derived Growth Factor)
. PDGF normally serves as a cell-to-cell signal, secreted
by platelets and diffusing to other cells such as fibroblasts and smooth
muscle cells, which it stimulates to grow and crawl about. If a cell produces
its own form of PDGF, it behaves as if it were being constantly exposed to
high concentrations of external PDGF; in other words, it stimulates its own
growth and locomotion without limit. This is called autocrine stimulation.
It is thought that the sis protein binds to the PDGF receptor proteins
while these receptors are in the cytoplasm (prior to their insertion into
the plasma membrane where their normal interaction with PDGF would have

erbB: Codes for an abnormal version of the membrane receptor
for the extracellular protein called epidermal growth factor.
This form of the receptor behaves as if it were constantly bound to molecules
of its growth factor, thus constantly sending a false signal stimulating
cell growth. A similar oncogene, called erbB-2 seems (based on its
base sequence) to code for a receptor for some other (still undiscovered)
growth factor. It is found in amplified form in about one fourth of all
human breast and ovarian cancers

ras: The function of its normal equivalent protein is to relay
and amplify stimulatory signals, such as those from growth factor receptors
It binds a molecule of GTP whenever it is itself stimulated. It then relays
stimulatory signals and continues to do so until its GTP is hydrolysed to
Certain specific amino acid substitutions eliminate this
protein's ability to hydrolyze bound GTP, however, so that it
remains permanently in its "on"
state, constantly "relaying"
non-existent signals for the cell to grow and divide. Such mutations of
this one oncogene are believed to be responsible for no fewer than
one fifth of all human cancers, including up to half of colon
carcinomas, and 90% of cancers of the pancreas
(Although note that several different ras genes are known.)
Out of 25 average people, ras will kill one of them!

src: Codes for a protein that spontaneously becomes concentrated
on the inside surface of the plasma membrane
, especially at the sites
of cell-substratum adhesion
. This protein is an enzyme (a tyrosine
) whose effect is to catalyze the covalent bonding of phosphate
groups onto the hydroxyl group of tyrosine amino acid residues of proteins.
The proteins phosphorylated by the src protein include some which participate
in the mechanical linkage between the actin cytoskeleton and materials to
which the outside surface of the plasma membrane attaches; these changes may
thus be responsible for weakening the cell's adhesiveness. Recent work in
Patricia Maness' laboratory in the UNC Biochemistry Department indicates
that the normal form of the gene functions in the chemotactic guidance of
nerve growth cones. The src protein was the first tyrosine kinase to
be discovered.
Since all previously discovered kinases (there are many
of them in the cell) had catalyzed the bonding of phosphates to the hydroxyl
groups of serines and threonines, it was first assumed that phosphorylation
of tyrosines was peculiar to cancer cells. But many normal tyrosine kinases
have subsequently been found.

myc: Codes for a nuclear protein whose normal function seems to be
as some kind of a transcription factor promoting cell growth
For example, when a normal cell is stimulated to grow and divide
(for example, by exposure to PDGF), then the c-myc gene product (protein)
temporarily increases in concentration; conversely, this gene normally becomes
inactive in non-mitotic cell types. Many human cancers have been shown
to have undergone amplification of the c-myc gene (often about 10 copies
of the gene) this includes many cases of leukemia and about 30% of lung
cancers of the highly lethal "small cell" type and breast cancers.
The progression of cancerous cells to ever more and more aggressive states
is frequently traceable to further amplification of the myc gene

bcl-2: This name stands for B cell lymphoma and the protein for
which this gene codes seems to have the normal function of inhibiting the
spontaneous death of B-lymphocytes. In order that the total number of
B cells in your body does not continue to increase without limit (because
of constant exposure to different antigens) it is essential that the great
majority of B-cells self-destruct. This self-destruction phenomenon
("apoptosis") will be discussed more fully below. When too much
bcl-2 protein is produced in a given B cell, this blocks the self-destruction
Trans-genic mice with duplications of the bcl-2 gene accumulate abnormal
concentrations of lymphocytes, among other abnormalities. Many human
lymphomas result from promoter or enhancer sequences of the antibody
(on the 14th chromosome) accidentally becoming spliced to the
site on the 18th chromosome where the bcl-2 gene is located
; whenever
these B cells "try" to make antibody molecules, what they make instead is
lots of the bcl-2 protein. These cells therefore accumulate to form a
slow-growing lymphoma (which is always fatal, although not usually until
one of the bcl-transformed clones has subsequently also been transformed by
an over-activity of the myc oncogene). Prior to this they grow slowly,
making it especially paradoxical that these lymphomas can be caused to
shrink almost to nothing by the use of growth-poisoning chemotherapeutic

* Note that most of the oncogenes listed above are part of a "chain of
command" by which external signals, especially protein growth factors,
normally stimulate cell growth and division
. A typical sequence of events
would be for a (A) growth factor molecule to diffuse up to a cell's outer
surface, then (B) bind to a membrane protein that serves as a specific
receptor for that growth factor, with the conformation (C) or other properties
of this receptor being changed by the binding, thereby causing either the
activation of a cytoplasmic enzyme (that might be a protein kinase or ),
or (D) the activation of a g-protein (such as the c-ras protein) that would then
(E) activate a protein kinase, which would phosphorylate various
cytoplasmic proteins, including some involved in cell adhesion, and would also
stimulate increased transcription and translation of (F) genes for
certain transcription factors such as c-myc. Paradoxically, myc also tends to
stimulate apoptosis (G), unless counteracted by other gene products such as bcl-2.

Cancer cells from actual patients usually contain over-active versions
of several different oncogenes, not infrequently 3 or 4 or more
Typically, there is one that acts at the nuclear level (such as myc) and
one or more (such as ras or src) that act at the cytoplasmic level.
For several years (between about 1982-86) it was confidently believed that
cancer wouldn't occur unless there were at least two, and that one of the two
had to be cytoplasmic in its action (like sis, erb, ras or src)
and that the other had to act at the nuclear level (like myc).
But this is no longer believed.

At current rates in the USA, 25% of you will get cancer.

Four-fifths of this 25% will die of their cancer.

That's 20 people out of every one hundred.


back to syllabus