Advancing our Understanding of Gastrointestinal Diseases

Transcript

00:00 --> 00:02Funding for Yale Cancer Answers is
00:02 --> 00:04provided by Smilow Cancer Hospital.
00:06 --> 00:08Welcome to Yale Cancer Answers with
00:08 --> 00:10your host doctor in Anees Chagpar.
00:10 --> 00:12Yale Cancer Answers features the
00:12 --> 00:14latest information on cancer care by
00:14 --> 00:16welcoming oncologists and specialists
00:16 --> 00:18who are on the forefront of the
00:18 --> 00:20battle to fight cancer. This week,
00:20 --> 00:22it's a conversation about using
00:22 --> 00:24chemical tools to detect cancer
00:24 --> 00:25causing proteins with doctor
00:25 --> 00:27Stavroula Hatzios.
00:27 --> 00:28Dr Hatzios is assistant
00:28 --> 00:30professor of molecular,
00:30 --> 00:31cellular and developmental
00:31 --> 00:33biology and of chemistry at the
00:33 --> 00:35Yale School of Medicine where
00:35 --> 00:37Doctor Chagpar is a professor of
00:37 --> 00:38Surgical oncology.
00:40 --> 00:42Maybe we can start off
00:42 --> 00:44by you telling us a little bit more
00:44 --> 00:46about yourself and what it is you do.
00:46 --> 00:48My background is in chemistry
00:48 --> 00:50and microbiology so not a
00:50 --> 00:52traditional cancer biologist,
00:52 --> 00:56but I use chemical tools to better
00:56 --> 00:58understand infectious diseases and
00:58 --> 01:00more specifically how microbes can
01:00 --> 01:03contribute to cancer in humans.
01:03 --> 01:06So in my training I started out by
01:06 --> 01:07researching infectious diseases,
01:07 --> 01:09particularly airborne pathogens.
01:09 --> 01:11Like Mycobacterium tuberculosis
01:11 --> 01:14that causes human tuberculosis,
01:14 --> 01:15but then as a postdoc,
01:15 --> 01:18I switched to studying
01:18 --> 01:19gastrointestinal pathogens,
01:19 --> 01:20principally vibrio cholera,
01:20 --> 01:22which is the bacterium that causes
01:22 --> 01:24the diarrheal disease cholera.
01:24 --> 01:25And it was through my postdoctoral
01:25 --> 01:28training that I began to engage in
01:28 --> 01:29conversations with other scientists
01:29 --> 01:31who recommended that I start applying
01:31 --> 01:33some of the chemical tools and
01:33 --> 01:36approaches that I was a developing
01:36 --> 01:37to study comparatively understudied
01:37 --> 01:39microbes like Helicobacter pylori.
01:39 --> 01:42And that was really my entry point into
01:42 --> 01:45the field of cancer microbiology and
01:45 --> 01:46cancer microbiology really refers to
01:46 --> 01:49an area of research that's emerging
01:49 --> 01:51where we're looking at how microbes
01:51 --> 01:54that indigenous microbes in our bodies.
01:54 --> 01:55Which comprise the microbiome,
01:55 --> 01:58as well as infectious microbes that
01:58 --> 02:01cause disease might contribute to the
02:01 --> 02:04development of cancer in humans or
02:04 --> 02:06alter outcomes of cancer therapies.
02:06 --> 02:07So I begin researching Helicobacter
02:07 --> 02:09pylori a little bit as a postdoc,
02:09 --> 02:10and that's really been the focal
02:10 --> 02:12point of my labs work.
02:12 --> 02:14Trying to understand how this very
02:14 --> 02:17important gastric or stomach pathogen
02:17 --> 02:20causes cancer in a subset of infected humans,
02:20 --> 02:22and what are the pathways the
02:22 --> 02:24molecular events by which cancer.
02:24 --> 02:26Develops and we use a lot of
02:26 --> 02:28chemical approaches to sort of
02:28 --> 02:30understand what those pathways are.
02:30 --> 02:33Yeah, so I was going to ask
02:33 --> 02:35something along the same vein.
02:35 --> 02:37Many people, when they think
02:37 --> 02:39about Helicobacter pylori or H.
02:39 --> 02:41Pylori, as it's sometimes
02:41 --> 02:43known we think about ulcers.
02:43 --> 02:45We don't really think about cancer.
02:45 --> 02:47So can you talk a little bit
02:47 --> 02:49more about the link between H.
02:49 --> 02:51Pylori and cancer and how how
02:51 --> 02:52you got started with that?
02:54 --> 02:55Absolutely yeah, H.
02:55 --> 02:57Pylori is a fascinating,
02:57 --> 02:58fascinating microbe.
02:58 --> 03:00As you mentioned,
03:00 --> 03:01it is primarily linked,
03:01 --> 03:04at least in public knowledge,
03:04 --> 03:07to peptic ulcers, stomach inflammation.
03:07 --> 03:09But it's also the leading risk
03:09 --> 03:11factor for gastric cancer,
03:11 --> 03:13which I think currently remains
03:13 --> 03:16the third leading cause of cancer
03:16 --> 03:17related deaths worldwide.
03:17 --> 03:19This is a microbe that's found
03:19 --> 03:22in half of the global population,
03:22 --> 03:25and for most people it it doesn't
03:25 --> 03:26lead to cancer.
03:26 --> 03:28It may actually be innocuous,
03:28 --> 03:30meaning it may not do too
03:30 --> 03:31much to the infected host,
03:31 --> 03:34but a subset of those who carry the
03:34 --> 03:37microbe as a normal part of their
03:37 --> 03:39stomach microbiome will develop peptic
03:39 --> 03:41ulcers and gastric inflammation,
03:41 --> 03:42called gastritis.
03:42 --> 03:44That's roughly 10 to 15%
03:44 --> 03:45of people who have H.
03:45 --> 03:48Pylori and then a much smaller percentage.
03:48 --> 03:501 to 3% typically go on to develop
03:50 --> 03:52gastric cancer and this connection
03:52 --> 03:55was only made a couple of decades ago
03:55 --> 03:57by Robin Warren and Barry Marshall,
03:57 --> 03:59who won the Nobel Prize in medicine in
03:59 --> 04:022005 for this discovery that this microbe.
04:02 --> 04:05Can cause peptic ulcers,
04:05 --> 04:07gastric inflammation and ultimately
04:07 --> 04:11cancer and in fact due to their work, H.
04:11 --> 04:12Pylori is now the first,
04:12 --> 04:15formally characterized or classified
04:15 --> 04:19microbe known to be a human carcinogen.
04:19 --> 04:20So in individuals who have H.
04:20 --> 04:21Pylori,
04:21 --> 04:25the microbe can cause chronic
04:25 --> 04:27inflammation of the gastric lining
04:27 --> 04:29and overtime and some hosts.
04:29 --> 04:32This can develop into gastric cancer.
04:32 --> 04:34And what's a major challenge for
04:34 --> 04:37those of us in the field is trying
04:37 --> 04:39to understand why it is that some
04:39 --> 04:41individuals develop cancer and others do not.
04:41 --> 04:44And that's a really important question.
04:44 --> 04:46The reason it's so important is
04:46 --> 04:47that typically if someone has H.
04:47 --> 04:48Pylori.
04:48 --> 04:50You can administer antibiotics
04:50 --> 04:52to get rid of microbe,
04:52 --> 04:54but these microbes have a
04:54 --> 04:55way of evolving very,
04:55 --> 04:57very rapidly and thus they
04:57 --> 04:59they evolve drug resistance,
04:59 --> 05:01which limits the number of drugs
05:01 --> 05:02that we have available to treat them.
05:02 --> 05:04So if you just administer in
05:04 --> 05:05a biotics to half the global
05:05 --> 05:07population to rid them of H.
05:07 --> 05:07Pylori,
05:07 --> 05:10that may not be the best approach
05:10 --> 05:11because you'll fuel the rise
05:11 --> 05:12of antibiotic resistance.
05:12 --> 05:14And there's also some emerging
05:14 --> 05:15thought that H.
05:15 --> 05:17Pylori may actually be beneficial to
05:17 --> 05:19some portion of the population since.
05:19 --> 05:21People carry this microbe,
05:21 --> 05:22usually from childhood,
05:22 --> 05:24and it can help train the immune
05:24 --> 05:26system similarly to how we think
05:26 --> 05:27of other microbes that are found
05:27 --> 05:29in our microbiome.
05:29 --> 05:31So trying to understand whom should
05:31 --> 05:33be treated with antibiotics and
05:33 --> 05:35when who is at risk of developing
05:35 --> 05:37cancer down the line.
05:37 --> 05:38That's a very important question,
05:38 --> 05:40and that's some of what our work
05:40 --> 05:41is focused on understanding.
05:42 --> 05:44So tell us more about that because
05:44 --> 05:46that that clearly is fascinating
05:46 --> 05:48when you think about you know so
05:48 --> 05:50much of the world's population.
05:50 --> 05:53Have this this bacteria you know
05:53 --> 05:55a reasonable proportion of them.
05:55 --> 05:58Get gastritis and ulcers and are
05:58 --> 06:00typically treated with as you say,
06:00 --> 06:05antibiotics and acid reducing medications.
06:05 --> 06:06But there is this subset
06:06 --> 06:08who go on to get cancer.
06:08 --> 06:11So what do we know about that population
06:11 --> 06:14and why it is that they are more
06:14 --> 06:16susceptible to developing malignancy?
06:18 --> 06:20Great question I. I think we don't fully
06:20 --> 06:22know and that's something that a lot
06:22 --> 06:25of research in the field is focused on.
06:25 --> 06:28We have some indications as a field as to
06:28 --> 06:31what might be increasing the risk among
06:31 --> 06:33certain individuals and those can range
06:33 --> 06:36from geography to diet to genetic background,
06:36 --> 06:38but there are challenges also in
06:38 --> 06:40making some of those associations.
06:40 --> 06:42So certainly there are certain parts
06:42 --> 06:44of the world in which the incidence of
06:44 --> 06:47H pylori associated gastric cancer.
06:47 --> 06:50Is higher particular parts of South America?
06:50 --> 06:54For example, there have been studies linking
06:54 --> 06:57altitude to the risk of developing H.
06:57 --> 06:58Pylori associated gastric cancer,
06:58 --> 07:00as well as the amount of salt in
07:00 --> 07:02the diet as well as iron levels.
07:02 --> 07:04So various environmental factors
07:04 --> 07:06are thought to increase risk and
07:06 --> 07:07certainly genetic predisposition
07:07 --> 07:10in some cases may play a role,
07:10 --> 07:12although we don't fully understand
07:12 --> 07:13what those factors may be.
07:13 --> 07:15A challenge there is that the
07:15 --> 07:18microbe is found in such a large
07:18 --> 07:19portion of the population.
07:19 --> 07:22That it can be difficult to identify
07:22 --> 07:23key factors that really predispose
07:23 --> 07:26subset to the development of cancer
07:26 --> 07:28risk and on the microbial side,
07:28 --> 07:30which I haven't really mentioned thus far.
07:30 --> 07:33The Microbit itself has a very complex
07:33 --> 07:35evolutionary history which in and
07:35 --> 07:36of itself is super fascinating.
07:36 --> 07:39It's thought to have Co evolved with humans
07:39 --> 07:42since several thousands of years ago,
07:42 --> 07:43over 60,000 years.
07:43 --> 07:46It's been with humans and thus the phylogeny.
07:46 --> 07:48Basically the evolutionary history.
07:48 --> 07:50How this microbe has evolved.
07:50 --> 07:52Can be used to trace migratory
07:52 --> 07:55patterns of the human, the human race,
07:55 --> 07:57and it's really thought that the
07:57 --> 08:00microbe evolves quite rapidly as well.
08:00 --> 08:02Once it's in a specific human host
08:02 --> 08:05and thus it can be very difficult
08:05 --> 08:07to assign specific microbial genetic
08:07 --> 08:09patterns with cancer risk.
08:09 --> 08:10Although there are,
08:10 --> 08:11I should note,
08:11 --> 08:13some important proteins and genes
08:13 --> 08:15that the microbe carries which
08:15 --> 08:17do correlate very strongly with
08:17 --> 08:19cancer risk in some individuals.
08:20 --> 08:25So, so how do we kind of move that forward?
08:25 --> 08:29I mean when we think about people who
08:29 --> 08:32you know present to their doctor with
08:32 --> 08:35stomach pain and and ulcers and gastritis,
08:35 --> 08:37they generally speaking will have
08:37 --> 08:39an endoscopy and a a small biopsy
08:39 --> 08:42will be taken and sent to the lab
08:42 --> 08:44and the lab will confirm that.
08:44 --> 08:47Yes indeed they have H pylori.
08:47 --> 08:48Is it, you know,
08:48 --> 08:50given what you just mentioned,
08:50 --> 08:52is it possible for that lab instead
08:52 --> 08:55of just saying yes, you have H.
08:55 --> 08:58Pylori to look at the particular
08:58 --> 09:01features of of that particular H.
09:01 --> 09:02Pylori and say well,
09:02 --> 09:05this particular brand of H.
09:05 --> 09:09Pylori has an increased risk of you
09:09 --> 09:11developing gastric cancer versus
09:11 --> 09:16another brand of the same bacteria.
09:16 --> 09:17Yes,
09:17 --> 09:20I do think that that's possible.
09:20 --> 09:22It is possible to culture the
09:22 --> 09:25microbes from from human samples
09:25 --> 09:27and assess at a genetic level
09:27 --> 09:30if the microbe contains these.
09:30 --> 09:31These risk factors,
09:31 --> 09:33and I think that's one possible approach.
09:33 --> 09:34Practically speaking,
09:34 --> 09:35it may be a bit challenging,
09:35 --> 09:38but as we have more advances with
09:38 --> 09:39regards to genome sequencing and
09:39 --> 09:42PCR based methods that can help us
09:42 --> 09:44identify these factors quickly,
09:44 --> 09:46I think that's one approach.
09:46 --> 09:48I think what is maybe more important
09:48 --> 09:52as we move forward in the field is
09:52 --> 09:54trying to identify early risk factors
09:54 --> 09:56because maybe one thing I haven't
09:56 --> 09:58mentioned is that gastric cancer
09:58 --> 10:01tends to present quite later in life,
10:01 --> 10:03so with with regards to H.
10:03 --> 10:03Pylori infection.
10:03 --> 10:04As I mentioned,
10:04 --> 10:06children usually are infected with
10:06 --> 10:08the microbe when they're very young.
10:08 --> 10:10Typically we believe through
10:10 --> 10:12household contacts with other family
10:12 --> 10:14members who have the microbe.
10:14 --> 10:16And it's not until decades later that
10:16 --> 10:18someone would present with gastric cancer.
10:18 --> 10:20So this very there's this very
10:20 --> 10:22long lag phase from, you know,
10:22 --> 10:24the infection in childhood to the
10:24 --> 10:25development of gastric cancer.
10:25 --> 10:27And once it's diagnosed,
10:27 --> 10:29it can be pretty late stage.
10:29 --> 10:31So that's also challenging in
10:31 --> 10:32terms of treatment.
10:32 --> 10:34And so I think what's needed
10:34 --> 10:36are ways to assess much earlier.
10:36 --> 10:38Whether or not someone is at
10:38 --> 10:39risk and one way,
10:39 --> 10:40as you mentioned,
10:40 --> 10:41could be looking at the microbe
10:41 --> 10:42and then others.
10:42 --> 10:44Others may be trying to identify.
10:44 --> 10:48Host factors that may be indicative
10:48 --> 10:50of of infections that may be heading
10:50 --> 10:52down the road towards cancer,
10:52 --> 10:54and that's what I think a lot of
10:54 --> 10:56research in this area is focused on,
10:56 --> 10:57including the work of my own lab,
10:57 --> 10:59is trying to identify effects that
10:59 --> 11:01microbes may have on the host
11:01 --> 11:04that could be translated into new
11:04 --> 11:05diagnostic tests and indications
11:05 --> 11:07of early cancer risk.
11:08 --> 11:10So, so tell us more about that in terms
11:10 --> 11:13of the work that's going on in your lab,
11:13 --> 11:16sure, so. What we're trying to do is
11:16 --> 11:20excuse me, is trying to understand.
11:20 --> 11:22How infection alters proteins in cells
11:22 --> 11:26that are found in the stomach in a in a
11:26 --> 11:28manner that may promote tumor growth.
11:28 --> 11:30So how is it that the microbe
11:30 --> 11:32interfaces with human proteins?
11:32 --> 11:34How do they alter?
11:34 --> 11:36How do those interactions alter the
11:36 --> 11:39proteins behavior in a manner that could
11:39 --> 11:41promote the development of cancer,
11:41 --> 11:42so to break it down a bit when
11:42 --> 11:44when you have an infection,
11:44 --> 11:46your body's immune system will
11:46 --> 11:48respond to try to clear the infection
11:48 --> 11:49and that that generally involves
11:49 --> 11:51the recruitment of immune cells.
11:51 --> 11:53And these immune cells will produce
11:53 --> 11:55a lot of oxidants or free radicals.
11:55 --> 11:57These are small molecules that
11:57 --> 11:59are very reactive.
11:59 --> 12:00They contain a lot of oxygen.
12:00 --> 12:01They're starved for electrons,
12:01 --> 12:03so they react very readily with
12:03 --> 12:05other molecules in your cells,
12:05 --> 12:06and they can cause damage to cells.
12:06 --> 12:09Because of this intrinsic
12:09 --> 12:10chemical reactivity.
12:10 --> 12:12And one of the major classes of
12:12 --> 12:14biomolecules that can get damaged by
12:14 --> 12:16these oxidants or proteins and proteins
12:16 --> 12:18are super important because they
12:18 --> 12:20do a lot of chemistry in ourselves.
12:20 --> 12:22They they generate energy,
12:22 --> 12:23they help cells grow.
12:23 --> 12:24They help them divide.
12:24 --> 12:26They provide structure to cells.
12:26 --> 12:28They help mediate interactions between cells,
12:28 --> 12:31and these are all very important processes
12:31 --> 12:33that if they become dysregulated,
12:33 --> 12:35so if they're interrupted or inhibited,
12:35 --> 12:37messed with in some way,
12:37 --> 12:40they could lead to the development of cancer.
12:40 --> 12:42And So what we're trying to understand
12:42 --> 12:45is when you have an infection and
12:45 --> 12:47all of these oxidants are produced
12:47 --> 12:48by the immune system,
12:48 --> 12:51some of those oxidants will damage proteins.
12:51 --> 12:53And when those proteins get damaged,
12:53 --> 12:56do they alter some of these processes
12:56 --> 12:59that could encourage cancer to form?
12:59 --> 13:01If that's the case in our data points,
13:01 --> 13:03to indicates that that is.
13:03 --> 13:05Then can we identify you?
13:05 --> 13:07Some of these proteins as new
13:07 --> 13:09diagnostic markers of cancer risk?
13:09 --> 13:11So if these proteins are getting
13:11 --> 13:11damaged early on,
13:11 --> 13:13can we use them as indicators that
13:13 --> 13:15cancer may be maybe more likely
13:15 --> 13:16down the line?
13:17 --> 13:19Yeah, so I was just about to say, I mean,
13:19 --> 13:21that sounds like just fascinating
13:21 --> 13:23work and and I'd really like to
13:23 --> 13:25dig a little deeper into into that.
13:25 --> 13:27But first we have to take a
13:27 --> 13:29short break for a medical minute.
13:29 --> 13:31So please stay tuned to learn more
13:31 --> 13:33information about research and to
13:33 --> 13:35detecting cancer causing proteins
13:35 --> 13:37with my guest doctor Stavroula Hatzios.
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14:54 --> 14:56Welcome back to Yale Cancer Answers.
14:56 --> 14:59I'm doctor Anees Chagpar and I'm joined
14:59 --> 15:01tonight by my guest doctor Stavroula Hatzios.
15:01 --> 15:03We're discussing some of her recent
15:03 --> 15:05research and right before the break
15:05 --> 15:07she was starting to tell us about H.
15:07 --> 15:09Pylori. Now, for those of
15:09 --> 15:11you who are just joining us,
15:11 --> 15:12you know each pylori.
15:12 --> 15:15It's that bacteria that sits in your
15:15 --> 15:17stomach and that causes ulcers and gastritis.
15:17 --> 15:19And things like that.
15:19 --> 15:22And we never really think about it
15:22 --> 15:25necessarily as being associated with cancer.
15:25 --> 15:27However, Savula tells us that it's actually
15:27 --> 15:31a leading cause of gastric cancer and
15:31 --> 15:34the mechanism for that is something that
15:34 --> 15:37she and her lab is working on discovering
15:37 --> 15:40because not everybody who has H.
15:40 --> 15:42Pylori gets gastric cancer.
15:42 --> 15:44Thank goodness, but some people do.
15:44 --> 15:46And so stavroula right before the
15:46 --> 15:49break you were telling us that one
15:49 --> 15:51of the potential mechanisms of this,
15:51 --> 15:53if I understood correctly,
15:53 --> 15:55is that with this.
15:55 --> 15:58Infection with this H pylori your
15:58 --> 16:01immune system starts to kind of
16:01 --> 16:03act on that infection.
16:03 --> 16:05It it kind of gets geared up as it
16:05 --> 16:08would to any infection and starts
16:08 --> 16:11manipulating some proteins and that those
16:11 --> 16:13proteins might actually signal cancer.
16:13 --> 16:14Is that right?
16:15 --> 16:17Yes, that's what we believe
16:17 --> 16:18and what we're investigating,
16:18 --> 16:21and so we think that a lot of the
16:21 --> 16:23inflammation that occurs during H.
16:23 --> 16:25Pylori infection, which is accompanied
16:25 --> 16:27by the production of oxidants.
16:27 --> 16:29Those small molecules
16:29 --> 16:30that are highly reactive,
16:30 --> 16:33leads to changes in your cells, the proteins,
16:33 --> 16:37the DNA that helps nucleate cancer formation,
16:37 --> 16:38and as you mentioned,
16:38 --> 16:39we're focusing on the proteins.
16:39 --> 16:42How do those change in a way
16:42 --> 16:44that may promote tumor growth?
16:44 --> 16:45Our lab is using.
16:45 --> 16:48Some advanced chemical tools that
16:48 --> 16:50allow us to identify specific
16:50 --> 16:52proteins and human gastric cells
16:52 --> 16:55that get damaged or modified by
16:55 --> 16:58these oxidants produced during H.
16:58 --> 16:58Pylori infection,
16:58 --> 17:01so we can basically canvas the whole
17:01 --> 17:03cell with these chemical tools and
17:03 --> 17:05say what proteins are you getting
17:05 --> 17:07modified by these oxidants and then
17:07 --> 17:10independently look at these proteins
17:10 --> 17:12using biochemistry and some biology.
17:12 --> 17:13Other very interesting
17:13 --> 17:15tools in our toolkit to ask.
17:15 --> 17:18What happens when these proteins are
17:18 --> 17:20modified that may promote tumor growth,
17:20 --> 17:22and for that we use a number
17:22 --> 17:23of different model systems,
17:23 --> 17:25both in the lab and using a number
17:25 --> 17:27of other different systems to look
17:27 --> 17:30at tumor growth as a result of
17:30 --> 17:32these modifications to the proteins,
17:32 --> 17:34the long term goal here is to
17:34 --> 17:36identify modified proteins that
17:36 --> 17:38could be used to diagnose cancer
17:38 --> 17:40risk much earlier in an infection.
17:40 --> 17:41So you might imagine,
17:41 --> 17:42as you mentioned previously,
17:42 --> 17:45if someone presents at a clinic with an H.
17:45 --> 17:46Pylori infection,
17:46 --> 17:49maybe there could be a biopsy taken
17:49 --> 17:51where we look specifically for
17:51 --> 17:54proteins that we've identified in the lab.
17:54 --> 17:57Promote tumor growth and see if
17:57 --> 17:59those have been changed in a way
17:59 --> 18:01that aligns with that outcome.
18:01 --> 18:04And if you can detect those small
18:04 --> 18:06molecular changes very early in
18:06 --> 18:08an infection that that may help
18:08 --> 18:10improve outcomes on the patient side
18:11 --> 18:14so that that's an interesting theory
18:14 --> 18:16stavroula, but one of the things
18:16 --> 18:18that you mentioned before the break,
18:18 --> 18:20which is true, is that there is
18:20 --> 18:23this lag time right between when
18:23 --> 18:24you get an infection when you have.
18:24 --> 18:27Gastritis and when you may ultimately
18:27 --> 18:29end up with gastric cancer,
18:29 --> 18:33are there ways that we can manipulate these
18:33 --> 18:38proteins or or reduce risk in some way?
18:38 --> 18:40Once we identify these proteins,
18:41 --> 18:43right? That is absolutely the goal.
18:43 --> 18:46So not only could such proteins
18:46 --> 18:48serve as indicators of cancer risk,
18:48 --> 18:51but the nice thing about proteins,
18:51 --> 18:52and particularly a lot of
18:52 --> 18:53the proteins that we study,
18:53 --> 18:56is that a lot of them carry enzymatic.
18:56 --> 18:57Function so there are enzymes.
18:57 --> 18:58That means that they can perform
18:58 --> 18:59different chemistry in the cell.
18:59 --> 19:02They can perform chemical reactions and
19:02 --> 19:05those are proteins that are really nicely
19:05 --> 19:07targeted by small molecules by drugs.
19:07 --> 19:09And thus if if these proteins
19:09 --> 19:12that are involved in the infection
19:12 --> 19:14response and down the line,
19:14 --> 19:16increasing the risk of tumor
19:16 --> 19:18growth can be targeted by drugs,
19:18 --> 19:20then you also have the opportunity
19:20 --> 19:21to develop new chemotherapeutics
19:21 --> 19:23that could help actually treat
19:23 --> 19:25cancers that result down the
19:25 --> 19:26line from these infections.
19:26 --> 19:28So not only are the proteins
19:28 --> 19:30important as diagnostic indicators,
19:30 --> 19:32but also carry the potential to
19:32 --> 19:34be new drug targets for actually
19:34 --> 19:36treating the cancer itself.
19:36 --> 19:38Wouldn't it be better if we were
19:38 --> 19:39able to somehow manipulate these
19:39 --> 19:41proteins to prevent cancer?
19:41 --> 19:43Is that something that's
19:43 --> 19:45being looked at? Yes, I think
19:45 --> 19:47we're not quite there yet.
19:47 --> 19:49We're still at the early stages
19:49 --> 19:50of trying to identify what these
19:50 --> 19:52proteins are and how they relate
19:52 --> 19:54to the time course of cancer
19:54 --> 19:55to the progression to cancer.
19:55 --> 19:57From the point of infection.
19:57 --> 19:59But yes, I think that there's
19:59 --> 20:01very much a possibility to
20:01 --> 20:03intervene at a very early stage.
20:03 --> 20:06If you do sort of a screen for such
20:06 --> 20:09proteins at early points of infection,
20:09 --> 20:11perhaps in in an ideal scenario.
20:11 --> 20:13In a case of a childhood infection,
20:13 --> 20:14for example,
20:14 --> 20:16and if you see this sort of indication,
20:16 --> 20:18then intervene at that point
20:18 --> 20:19with these drugs that I mentioned
20:19 --> 20:21might be down the line to kind
20:21 --> 20:23of inhibit the activity that
20:23 --> 20:24could lead to tumor development.
20:25 --> 20:26You know you mentioned that
20:26 --> 20:28half the world's population.
20:28 --> 20:30Actually carry this Helicobacter pylori in
20:30 --> 20:33our stomachs and for the majority of us.
20:33 --> 20:36Thank goodness we never have any problems.
20:36 --> 20:38There's a subset that get ulcers
20:38 --> 20:41and a subset even smaller that
20:41 --> 20:43that goes on to get cancer.
20:43 --> 20:47And I wonder whether.
20:47 --> 20:50The latter subset who get cancer is
20:50 --> 20:54a subset who actually get ulcers
20:54 --> 20:58versus they can get cancer without
20:58 --> 21:01having that intervening gastritis,
21:01 --> 21:03inflammation, kind of phase.
21:03 --> 21:05In other words,
21:05 --> 21:09if I have an asymptomatic infection with H.
21:09 --> 21:12Pylori and I just carry this,
21:12 --> 21:14but it never really bothers me.
21:14 --> 21:16Am I at the same risk of
21:16 --> 21:17getting gastric cancer?
21:17 --> 21:19As a result of carrying that bug,
21:19 --> 21:23as I would be if I not only carried H.
21:23 --> 21:24Pylori but that H.
21:24 --> 21:26Pylori went on to give me gastritis
21:26 --> 21:29and ulcers and so on and so forth.
21:29 --> 21:31And then I get gastric cancer.
21:31 --> 21:32Do you understand my question?
21:33 --> 21:34Yeah, I think so.
21:34 --> 21:36And I should note again that I'm not
21:36 --> 21:38a clinician, so this is certainly
21:38 --> 21:41not my my area of expertise.
21:41 --> 21:42But I will say my understanding
21:42 --> 21:44is that the latter holds true,
21:44 --> 21:47so those individuals who do develop ulcers.
21:47 --> 21:48You know, chronic inflammation.
21:48 --> 21:51Gastritis are the subset that are at
21:51 --> 21:52greater risk for developing cancer
21:52 --> 21:55down the line and the the model in
21:55 --> 21:57the field is that each pylori induces
21:57 --> 22:00infection in some host induces this
22:00 --> 22:02chronic inflammation and in some
22:02 --> 22:04hosts and some humans who have the.
22:04 --> 22:06The microbe overtime that leads to
22:06 --> 22:08the development of this inflammation
22:08 --> 22:10in the tissue and that process is
22:10 --> 22:12what seeds the development of the
22:12 --> 22:14cancer decades down the line as well.
22:14 --> 22:15So it does correlate strongly
22:15 --> 22:17with the incidence of inflammation
22:17 --> 22:19and people who have each pylori
22:20 --> 22:21and that makes so much sense because
22:21 --> 22:24we've seen that in other cancers as well,
22:24 --> 22:27where it really is. This inflammation,
22:27 --> 22:29the damage to the tissues.
22:29 --> 22:32This idea that you get inflammation?
22:32 --> 22:33You get fibrosis.
22:33 --> 22:36You get free radicals.
22:36 --> 22:40You you get, you know, an area of
22:40 --> 22:46tissue which is not as well perfused.
22:46 --> 22:49That can lead then to
22:49 --> 22:51cancers and and so you know,
22:51 --> 22:54presumably the tests that you're
22:54 --> 22:57developing to look at these these
22:57 --> 22:59infections might be something that
22:59 --> 23:02very easily could be done at the time
23:02 --> 23:04that somebody presents for a biopsy.
23:04 --> 23:05Diagnosing the H.
23:05 --> 23:08Pylori to begin with when they
23:08 --> 23:11they have symptoms of gastritis.
23:11 --> 23:12The next question is,
23:12 --> 23:16you know if we know that it is the
23:16 --> 23:18case that you know these gastric
23:18 --> 23:21cancers tend to emerge in an area
23:21 --> 23:23of inflammation and we we can kind
23:23 --> 23:26of see in your research and that
23:26 --> 23:28of others that the the pathway
23:28 --> 23:31seems to be these free radicals.
23:31 --> 23:34These small molecules and and damage to
23:34 --> 23:37proteins and an inflammatory response,
23:37 --> 23:40and so on and so forth.
23:40 --> 23:43With your chemical toolbox where you're
23:43 --> 23:45looking at these altered proteins.
23:45 --> 23:48Have you looked at that in
23:48 --> 23:49other cancers as well,
23:49 --> 23:53and isn't necessarily the case that
23:53 --> 23:57these are always related to microbes?
23:57 --> 24:00Or is it possible that some inflammation
24:00 --> 24:03may be due to other causes,
24:03 --> 24:05but that the end pathway,
24:05 --> 24:07the end result in terms of the small
24:07 --> 24:08molecules and the tissue damage
24:08 --> 24:11and the protein damage, et cetera?
24:11 --> 24:13With the inflammatory response is the same?
24:15 --> 24:17That's a great observation.
24:17 --> 24:19And yes, I think it is very likely to
24:19 --> 24:22be the case that a lot of these same
24:22 --> 24:24protein damage pathways are are shared
24:24 --> 24:26or are common amongst other cancers.
24:26 --> 24:28We specifically, my lab specifically
24:28 --> 24:31has not looked at other non
24:31 --> 24:33infection associated cancers,
24:33 --> 24:35but other labs have begun looking
24:35 --> 24:37at this question and have certainly
24:37 --> 24:40done it in other contexts as well,
24:40 --> 24:43and I think that there will be an emerging
24:43 --> 24:46picture of some proteins that get damaged.
24:46 --> 24:49By inflammation and oxidative stress
24:49 --> 24:52and variety of contexts and that these
24:52 --> 24:54may provide very important clues
24:54 --> 24:57for the risk of cancer development,
24:57 --> 25:00and I should also mention that one thing
25:00 --> 25:02that we haven't touched on is DNA damage,
25:02 --> 25:04which is perhaps the more well
25:04 --> 25:06known target of these oxidants that
25:06 --> 25:08are generated during inflammation.
25:08 --> 25:10And that's something that is certainly
25:10 --> 25:12very common across many different types
25:12 --> 25:15of cancers resulting from infection or not.
25:15 --> 25:17Oxidants can damage DNA.
25:17 --> 25:17Directly,
25:17 --> 25:20and that can lead to mutations and
25:20 --> 25:22instability of the genome that ultimately
25:22 --> 25:24helps seed cancer formation as well.
25:25 --> 25:28Yeah, the the problem with that though,
25:28 --> 25:29is that as you mentioned,
25:29 --> 25:31the nice thing about proteins is that
25:31 --> 25:33potentially you can do something about it.
25:33 --> 25:35So are people looking at, you know,
25:35 --> 25:38trying to figure out how you can
25:38 --> 25:41manipulate the system so that.
25:41 --> 25:44You can kind of counteract DNA damage.
25:44 --> 25:45My perception is that that's
25:45 --> 25:46a little bit more difficult.
25:47 --> 25:49I think you're right. Yeah, I'm not.
25:49 --> 25:51I'm not familiar with specific work in
25:51 --> 25:54that area, and I think it's it's a very
25:54 --> 25:56important point that the benefit the
25:56 --> 25:59advantage to looking at proteins, which
25:59 --> 26:01is still a very emerging area of research,
26:01 --> 26:03is that you have the opportunity to
26:03 --> 26:05intervene and actually do something about it.
26:05 --> 26:08And they also have the added advantage
26:08 --> 26:10of being both diagnostic indicators
26:10 --> 26:13or providing some some clues.
26:13 --> 26:15What might be to come down the line,
26:15 --> 26:17but also an opportunity to
26:17 --> 26:19intervene through drugs?
26:19 --> 26:20Small molecule approaches to
26:20 --> 26:22help alter these outcomes?
26:22 --> 26:22So I think for us,
26:22 --> 26:24that's why there's such an
26:24 --> 26:26exciting area of research,
26:26 --> 26:28particularly as they relate to microbes.
26:28 --> 26:31Yeah, you know, as you were talking about
26:31 --> 26:34kind of these pathways and the way that H.
26:34 --> 26:37Pylori works in terms of
26:37 --> 26:39gastric cancer by you know,
26:39 --> 26:42kind of getting the immune system to
26:42 --> 26:44respond to it and then creating these.
26:44 --> 26:48Small molecules and inflammation and so on.
26:48 --> 26:50It. It made me think about other
26:50 --> 26:53infections that we know also cause cancer,
26:53 --> 26:56but that are not bacterial so we know H.
26:56 --> 26:59Pylori is a is a little bacterium
26:59 --> 27:01that lives in our stomachs.
27:01 --> 27:03But we also know that many other
27:03 --> 27:05cancers are caused by viruses.
27:05 --> 27:09So thinking about hepatitis, for example,
27:09 --> 27:12the pathway seems to be very similar
27:12 --> 27:14in terms of you know, creating.
27:14 --> 27:16Inflammation and fibrosis and free
27:16 --> 27:19radicals and so on and so forth.
27:19 --> 27:22Is there a difference in terms
27:22 --> 27:25of how bacteria and viruses work
27:25 --> 27:28in terms of developing cancer?
27:28 --> 27:31And is it possible for your
27:31 --> 27:33research to potentially look at
27:33 --> 27:35virally mediated cancers as well?
27:36 --> 27:39Sure, I think that there are opportunities
27:39 --> 27:41to apply similar approaches to viral
27:41 --> 27:44infections that are associated with cancer.
27:44 --> 27:48And of course a lot of viruses have been
27:48 --> 27:51connected to very important malignancies,
27:51 --> 27:52HPV, human papilloma virus,
27:52 --> 27:54and cervical cancer.
27:54 --> 27:56That's perhaps one of the
27:56 --> 27:57most well known connections,
27:57 --> 27:59but there are several others,
27:59 --> 28:02like hepatitis C, Epstein Barr virus,
28:02 --> 28:04and the link between viruses and
28:04 --> 28:06cancer has been explored for
28:06 --> 28:09quite a long time and a lot more is
28:09 --> 28:13known about how viruses can engage with
28:13 --> 28:16the human cell to to cause cancer.
28:16 --> 28:18So some of the pathways may be similar,
28:18 --> 28:20but we think that they may also be
28:20 --> 28:22very distinct with regards to microbes,
28:22 --> 28:23but at the same time,
28:23 --> 28:25these approaches I think will be
28:25 --> 28:26very valuable for assessing viral
28:26 --> 28:28infections and finding common pathways.
28:29 --> 28:31Doctor Stavroula Hatzios is an
28:31 --> 28:32assistant professor of molecular,
28:32 --> 28:35cellular and developmental biology and of
28:35 --> 28:38chemistry at the Yale School of Medicine.
28:38 --> 28:40If you have questions,
28:40 --> 28:42the address is canceranswers@yale.edu
28:42 --> 28:45and past editions of the program
28:45 --> 28:47are available in audio and written
28:47 --> 28:48form at yalecancercenter.org.
28:48 --> 28:51We hope you'll join us next week to
28:51 --> 28:52learn more about the fight against
28:52 --> 28:54cancer here on Connecticut Public Radio.
28:54 --> 28:57Funding for Yale Cancer Answers
28:57 --> 29:00is provided by Smilow Cancer Hospital.

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June 26, 2022

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