Jack: Hi everyone and today's lecture
will be beginning our discussion of the epidemiology
of colon cancer,
by talking about the biology,
global trends and pathogenesis.
The goals of this lecture
are to describe the global burden of colorectal cancer.
Describe the anatomic pattern of colorectal cancer.
Define the high fat, low fiber hypothesis of Burkitt
and to discuss mechanisms of pathogenesis.
So to begin with,
we see that colorectal cancer is more common
in high income countries
compared to low and middle income countries.
In high income countries,
colorectal cancer mortality ranks third
behind only lung cancer and breast cancer.
Whereas in developing nations, it ranks sixth.
We also see this pattern repeated
when looking at mortality rates
being particularly high in parts of Eastern Europe
and Western Europe and Northern Asia.
In the United States, colon cancer in 2020
was responsible for 11.4 cases per 100,000,
with a slightly higher incidence rate in men than in women.
Overall, there were 5.4 colorectal cancer deaths per 100,000
in the US in 2020, with again, the mortality rate for men
being slightly higher than that of for women.
As with most other solid cancerous tumors,
colorectal cancer evolves over a period of years
and even decades.
Approximately 65 to 70% of large bowel cancers
develop in the descending sigmoid colon and rectum
and the remainder developed in the transverse
and ascending portions of the colon.
More than 95% of colorectal cancers
are denso carcinomas and many of them secrete mucin.
Carcinomas of the sigmoid colon and rectum
often grow, grow in an annular fashion,
producing so-called napkin ring constrictions
and obstruction of the bowel.
Carcinomas of the ascending colon
tend to extend along the bowel wall
and are much less likely to cause obstruction.
Colorectal cancer often develops
as a sequential series of steps,
beginning with focal dysplasia and hyperplasia
of the epithelial lining
and progressing to the formation of a adenomatous
and villous polyps.
Carcinoma in situ and ultimately invasive cancer.
Colon carcinogenesis invariably
progresses in the presence of inflammation.
Risk factors for colorectal cancer
include both lifestyle factors and genetic syndromes.
The comprehensive epidemiologic evidence
suggests that colorectal cancer
is largely influenced by these lifestyle factors.
So the risk of colorectal cancer development
is increased by diets high in fat and low in fiber,
sedentary lifestyles, obesity, alcohol and tobacco use,
and deficiencies in vitamin D, calcium,
and possibly selenium.
Genetic syndromes involving mutant mismatch repair genes
and tumor suppressor genes
account for only a small percentage of of cases.
Denis Burkitt formulated the high fat, low fiber hypothesis
of colon cancer.
This hypothesis is based upon the low incidence
of colon cancer and other intestinal diseases
in the African continent,
where Burkitt conducted his surgical practice.
In populations consuming a high fiber low fat diet,
Burkitt observed virtually none of the large bowel diseases
that are commonplace in westernized societies
such as hemorrhoids, diverticulosis, diverticulitis,
ulcerative colitis, Crohn's disease, and colorectal cancer.
His recommendations for prevention of colon cancer
specify high levels of intake throughout life.
40 grams of fiber daily with a high proportion of brand.
Protective mechanisms of fiber within the large bowel
can be broadly divided into that for soluble
and insoluble fiber.
Increasing the level of insoluble fiber
increases fecal bulk, thereby reducing transit time
and diluting the concentration of toxic
and carcinogenic compounds.
Soluble fiber binds to bile acids and bile salts
that may irritate the colorectal mucosa.
Furthermore, soluble fiber is fermented
to single chain fatty acids, such as beauty rate
that maintain homeostasis of cell proliferation
and apoptosis.
Animal studies,
suggests that colorectal protection depends on the type
and level of fiber and wheat brand
and that wheat brand inhibits tumor development
more consistently than other sources of fiber.
The totality of evidence generated thus far
remains compatible with Burkitt's original hypothesis.
The diet's high in fiber, particularly wheat brand fiber
provides significant protection
against the development of colorectal cancer.
Marked increases in the rates of colorectal cancer
in some developing countries
have also been linked to higher levels of fat intake.
A striking example is the Japanese population
wherein rates have risen from the lowest to the highest
in the world over the past 50 years.
In close parallel,
with the increase in per capita fat calories.
There's a hypothesis that colon cancer development
is linked to high intake of dietary fat
that upsets the balance of gut flora.
This hypothesis was based upon the historic low rates
of colorectal cancer in Japan
compared to high rates in the US,
corresponding to their low and high fat diets respectively.
Many subsequent epidemiologic investigations
have consistently found that the risk of colorectal cancer
increases with high intake of saturated fat in animal fat
and reciprocally that the risk is reduced
with increased intake of fish and fish oil.
Willie and colleagues found that American women
who ate beef, pork or lamb daily had a 2.5 fold higher risk
compared to women reporting little or no consumption.
In an investigation conducted in 24 European nations,
increasing the intake of omega-3 fatty acids from fish
and fish oil conferred significant protection
against colon cancer development.
Animal studies are in general agreement
with the epidemiologic evidence
in finding that a high amount of omega-6 fatty acids
from beef, corn oil or lard in the diet
enhances chemically induces tumor development
in lab animals and reciprocally
that the increasing the intake
of omega-3 fatty acids from fish, fish oil and olive oil,
decreases carcinogenesis.
In studies of migrants from low risk to high risk regions,
the rates of colon cancers show dramatic increases
after single generation,
suggesting that the risk for tumor development
in the large bowel increases rapidly with transition
to a high fat diet.
Mechanistically, it's theorized that diet's high in fat
promotes secretion of bile acids from the liver
and biliary tree.
These bile acids are dehydrogenated
to form the carcinogenic metabolites.
In addition, diet's high in fat typically contains steriles
which have mitogenic activity.
A key high risk enzyme is beta glucanase
which is responsible for hydrolysis of sterile conjugates
so that they may be recirculated.
It's also been noticed
that a gradient of colorectal cancer rates
is associated with latitude.
That is rates become higher in populations
that are further away from the equator.
It's been hypothesized that colon cancer development
may be related to a lack of vitamin D
due to decreased exposure to sunlight
and populations further away from the equator.
Activated vitamin D is necessary
for the absorption of dietary calcium
and important mineral for the maintenance
of physiologic homeostasis in the human body,
particularly the regulation and control
of cell division and the cell cycle.
In proliferating cell populations
like the colorectal mucosa.
Higher levels of vitamin D and calcium intake
have also been found
to reduce the risk of colorectal cancer
in several epidemiologic studies.
The relationship of vitamin D and cancer mortality
was examined in the third
National Health and Nutrition Examination Survey.
Baseline levels of serum 25 hydroxylated vitamin D
were measured in more than 16,000 participants
aged 17 years and older.
Individuals with serum vitamin D levels
of 80 animals per liter or higher at baseline
experience a 72% reduction in colorectal cancer mortality
compared to individuals with levels
lower than 50 animals per liter.
Despite the beneficial impact of vitamin D
in calcium observed in epidemiologic studies,
a randomized clinical trial involving postmenopausal women
of the Women's Health Initiative failed to show any benefit.
In at study daily supplementation of calcium and vitamin D
for seven years had no effect
on the incidence of colorectal cancer.
The long latency associated
with the development of colorectal cancer
in the limited seven year duration of the trial
may have contributed to this null finding.
Finally, so as we just noted some studies show mixed results
regarding the high fat, low fiber hypothesis of colon cancer
and considering what we know
about Hill's criteria of causality,
it's important to conduct further independent studies
and to look at the total available evidence
when trying to conclude what factors might be risk factors
or protective factors for colon cancer.
I also want to point out that studies
may have been hampered by the difficulty
of conducting randomized control trials,
which can be expensive.
They can last a long time
and it can be difficult to recruit participants
for such studies.