[MUSIC]
We are the
paradoxical A. Bipedal, naked, large brain.
Long the master of fire, tools,
and language, but still trying to understand ourselves.
Aware that death is inevitable.
Yet filled with optimism.
We grow up slowly.
We hand down knowledge.
We empathize, and the scene.
We shape the future from
our shared understanding of the past.
Carta brings together experts from diverse disciplines to
exchange insights on who we are and how we got here.
An exploration made possible by
the generosity of humans like you.
[MUSIC]
Hello, everyone and welcome to this short talk,
where I was going to talk about
the incidence of carcinomas in humans,
and why that could be a little special.
Here, this first slide shows a comparison of causes of
death from various diseases in 1900 versus 2010.
As you can see way back in 1900,
most of the causes of disease in
humans showed up as infectious diseases.
Whereas in 2010, most of the causes of
death in humans was either cancer or heart disease.
What are the criteria for human-specific disease?
Well, should be very commonly seen in
humans and rarely reported
in closely related species such
as the great apes, even in captivity.
Malignant neoplasms or cancers appear in
humans at different ages some
appearing in very young children,
like neuroblastoma and Wilms' tumor.
However, spontaneously occurring carcinomas,
carcinomas are malignancies of
epithelial cells of the breast,
stomach, colon, lung,
ovary, prostate, cervix, uterus, pancreas,
et cetera, are common in older human populations.
On the right there,
I put in some pathology gross pictures
of lesions I had seen.
The top one showing a lobe of
the lung with a primary cancer right there,
the next one shows an ulcerated carcinoma
at the junction of the esophagus and stomach,
and the next one is a breast carcinoma.
This is actually showing the
typical bit that you see in cancer,
is called cancer because it's a crab,
it extends into the surrounding tissue.
These carcinomas are also the ones most associated with
various environmental factors such as
diet and reproductive activity.
Like humans, great apes have been
reported to develop malignancies,
but most of these malignancies arise in the blood cells,
also called leukemias and lymphomas,
and in mesenchymal tissues called sarcomas.
However, spontaneously occurring carcinomas
seem very rare in the non-human primate.
The reason for the apparent rarity
of carcinomas in great apes are unknown.
Benign tumors of some of these organs have been
reported indicating that surveillance has been adequate,
thus it is possible that
these carcinomas will begin to be reported
great apes as captive populations continue to age.
Epithelium, in putting on my teaching hat here.
Epithelium, epi, meaning outside,
thelium means a cloak.
Epithelial cells are those cells
that communicate with the outside world.
Squamous, the epithelium lining the skin,
ear canal, anus,
cervix, vagina, esophagus.
Columnar, cells lining the trachea and lungs,
lining the GI tract,
the genitourinary tract,
cells of the liver, cells of
the pancreas, it makes enzymes.
Cuboidal epithelium of the kidney tubules,
ovarian follicle.
Transitional epithelium for the bladder and ureter.
Endothelium is another term.
It's one layer of
squamous epithelium that lines the blood vessels,
but there is no communication with the outside,
and so this is called the endothelium,
lines all the blood vessels.
During embryogenesis, the three
germ layers, endoderm, ectoderm,
mesoderm differentiate into
epithelia and nonepithelial cells,
which eventually form differentiate tissues and organs.
Epithelial cells rise from stem cells and
often line body surfaces that
interact directly with the outside.
They are typically attached to
the underlying connective tissue by a basement membrane.
The underlying stroma includes;
blood vessels, lymphatic vessels, hematopoietic cells,
stromal fibroblasts, extracellular matrix,
neuronal structures, smooth muscle,
adipose tissue, et cetera.
Benign tumors is a new growth of cells which form a lump,
but they don't invade the basement membrane,
like you'd see in a polyp, or a lipoma,
fibroadenoma, leiomyomas,
which are also called fibroid tumors.
Carcinomas arising from epithelial cells are
invasive and can metastasize
to different organs as shown here.
There's metastasis to the liver.
Here's a metastasis in the brain cerebellum.
Carcinomas, as I explained before,
arises skin, cervix, esophagus,
and lung, and then adenocarcinomas are gut,
lung, prostate, breast, et cetera.
Sarcomas arise in supporting
tissue and can be also invasive,
like the lymphomas, melanomas,
glioblastomas, osteosarcomas, fiber sarcomas, et cetera.
But today we're talking about carcinomas,
those arising from the epithelial cells
and which invade and metastasize.
This is an example of a lymphoma on the right,
on the left is a picture of a benign lymph node with
the T-cells and the B-cells and medulla and so on.
Whereas on the right is an example of a lymphoma,
where these lymphoid cells have proliferated and form
large and small follicles and have
infiltrated into the surrounding adipose tissue.
Lymphomas are the kind of tumors
or malignancies that most other vertebrates get,
and even some of the rodent models that
have been used, as they age,
they end up getting lymphomas,
but the carcinomas are pretty rare.
I'll go over a couple of
pieces of literature that's out there.
The first one here was published in 2009,
talking about neoplasia in the chimpanzee.
There, they described
about 105 spontaneous and 12 experimental neoplasms.
Seventy-four of those spontaneous tumors
occurred in females,
24 in males, seven in other animals.
Of the spontaneous tumors,
89 were benign, 14 were malignant,
and two were undetermined.
Most of these malignant tumors were unusual, rare tumors,
carcinomas of the biliary tract,
which are rare in humans but were
noticed in this particular chimp population.
The next publication I wanted to highlight was
this write up by Dr. Finch.
Evolution of human lifespan and diseases
of aging, back in 2010.
He wrote chimpanzees and
other primates appear to develop much less neoplasia.
He remarked that
no spontaneous mammary carcinomas have been reported.
In male 25 in years and older,
there's benign prostatic hyperplasia,
but no neoplasia was noted.
The next one,
and going in order of chronology in 2015,
we had written up an observation.
The apparent rarity of
epithelial carcinomas in captive chimpanzees.
Because above one in three humans
in developed countries will develop a carcinoma,
but this is rare in captive chimpanzees.
The simple ascertainment bias is
an unlikely explanation as
these nonhuman hominids are
recipients of excellent veterinary care
and research facilities and zoos,
and are typically subjected to necropsies when they die.
In keeping with this notion,
benign tumors and cancers that are less common in
humans are well documented in this population.
Dr. Loewenstein and colleagues in 2016
then published a comparative pathology of
aging great apes looking at bonobos,
chimpanzees, gorillas, and orangutans.
Commented that neoplasms common to
aging humans and apes include,
uterine leiomyomas,
which are those fibroid tumors in chimpanzees.
But other tumors of
elderly humans such as breast, prostate,
lung, colorectal cancers are uncommon in apes.
Then a group at Yerkes in 2017,
looked at 35 years of chimpanzee pathology and
observed 1,362 spontaneous pathology
lesions observed at necropsy or biopsy.
Cardiomyopathy was the most frequent lesion
observed at the time,
but no mention about neoplasia.
The same group again reported cause of
death analysis over that same 35-year period,
again showing cardiomyopathy is
a primary cause with no mention of neoplasia.
But in a table that was included,
they showed that carcinomas were observed in
about four of the chimpanzees
that they did the necropsies on.
They do mention that leiomyomas
of the uterus were also observed.
But these carcinomas were
those odd ones of
the biliary tract and so on that are rare in humans.
Now, segue into the possible rules,
the sialic acids and certain Siglecs in adding
fuel to the fire allowing
these carcinomas to occur in humans.
This is an introduction to
the diversity and cell surface sialic acids.
Everyone's heard about DNA,
making RNA, making protein.
But the cell is not done until
the cell surface glycans are made.
At the very tips of these glycans,
are these diamond-shaped objects called sialic acids.
These sialic acids are found on
the surfaces of every cell where
the squamous or columnar or
cuboidal epithelium or whatever.
These sialic acids are really
important in interacting with circulating lymphocytes,
monocytes, platelets, tumor cells, pathogens,
and influence the progression and spread of
human malignancies and
certain aspects of human evolution,
regulation, immune response and micro binding, etc.
There are two major kinds of
sialic acids on the mammalian cell surface.
For ease, we've call them Neu5Ac and Neu5Gc.
The humans had an inactivation of the CMAH enzyme,
the gene was inactivated about 2-3 million years ago.
Humans can only make
Neu5Ac and cannot convert to make Neu5Gc.
Chimps and bonobos and gorillas and
orangutans have both Neu5Ac and Neu5Gc,
but humans only have Neu5Ac
because of the lack of that gene.
The consequence of not having the CMAH gene,
and lots of Neu5Gc.
We think maybe due to the fact that when
we ingest Neu5Gc in food,
eating four-legged animals, they're shown here,
that Gc gets incorporated into the epithelium.
We've shown in publications over the last couple of
decades that all humans make anti-Neu5Gc antibodies.
Those circulating anti-Neu5Gc antibodies,
along with the Neu5Gc incorporation in
the epithelium contributes to
a chronic inflammation which is we are terming,
xenosialitis, "xeno" because the Gc comes from outside,
"sia" sialic acid "itis" inflammation.
We've proposed that in
several publication that this is what possibly
complicates atherosclerosis because we've see
Neu5Gc in the endothelium and atheromas.
Also this xenosialitis chronic inflammation
contributing to cancer occurrence.
This next slide shows
a Neu5Gc expression in endothelium and in
some normal tissues like prostate cancer
and coelomic epithelium and
in the blood vessels there as well.
But when you get cancer like ovarian carcinomas,
there's a lot of expression in
Neu5Gc in the endothelium and in the cancer as well,
ovarian prostate, colon, etc.
That was the Neu5Gc story
and many of you heard that before.
Now, a little bit on Siglecs.
This is a nice cartoon I thought I'd
share to show the Siglec interaction with
sialic acid on
the cell surface regulating immune homeostasis,
immune escape by pathogens and cancer cells as well.
Among this group of cell surface proteins known as
sialic acid binding immunoglobulin
like lectins or Siglecs.
The CD33 related Siglecs are found in
innate immune cells and are involved in cell signaling.
One Siglec, however,
appears to have gone rogue in
humans Siglec-XII encoded by the gene
Siglec-XII no longer bind sialic acid
and seems to be involved in
abnormal cell signaling in humans.
It can also play a role in cancer progression and help
explain why humans have
a much higher incidence of carcinomas,
cancers that arise from epithelial cells
where Siglec-XII was abundant than other great apes.
Only about 30 percent of humans produces rogue protein.
Most people have a mutation that inactivates Siglec-XII.
Comparing cohorts or cancer patients,
we found that functional Siglec-XII was associated with
a poor prognosis in
late stage colorectal cancer patients.
This is that graph from that paper
showing that the number of patient,
there's a high percentage of patients in
this advanced colorectal cancer cohort
that express Siglec-XII,
and those patients did poorly,
the overall survival was much less
than the patients that did not express Siglec-XII.
The abundance of expression of
carcinomas malignancy arising from
epithelia with a much higher expected frequencies
of Siglec-XII in cancers.
In normal people Siglec-XII is
only expressed in about 30 percent of people.
But in cancers 80 percent of cancers expressed it.
Advanced carcinomas are much more likely to occur in
individuals who have an intact Siglec-XII gene,
likely because the encoder relate to
our protein and Shp2 relate to oncogenic pathways.
These two are working on the mechanism there.
This is just a panel to show you
the multiple carcinomas that were examined in that study.
We looked at squamous carcinomas and adenocarcinomas
and showed a high expression in the squamous carcinomas.
There were a few that didn't really express Siglec-XII,
and the adenocarcinomas also,
there was a high expression,
but not as much as in the squamous carcinomas.
Squamous carcinomas are those that
arise in the head and neck, the tongue,
the oral cavity, the esophagus,
cervix, and so on.
Thank you for your attention during
this time when I tried to explain little bit of
some research that's been ongoing as to
why carcinomas are so prevalent in the human population,
as opposed to what is seen in the great apes.
Thank you. [MUSIC]