The Place Tumors Call Home

Resonance is a student-run podcast aimed at showcasing the science at Baylor through the eyes of young professionals. Each episode is written and recorded by students who have a passion for research and the medical community. Guests on the show include both clinical and basic science research faculty who are experts in their fields.

Dr. David Rowley discusses his career path and how he ended up researching cancer microenvironments. He delves into the biological mechanisms of tumor microenvironments and talks about what excites him most about this particular research field in the future.

Erik: And we are here. This is the Baylor College of Medicine Resonance podcast. I am one of your hosts, Erik Anderson.

Brandon: And I am Brandon Garcia, another host.

Phillip: And I'm Phillip Burkhart, the writer for this episode.

Erik: And so today we're gonna be talking with Dr. David Rowley about the tumor microenvironment and basically what that is and a little bit about his research on that over the past couple of years, or past many years. But to begin we wanted to give a little bit of background on what the tumor microenvironment is and also just cancer in general, so Philip, you want to help us out with that?

Phillip: Yes, so when thinking about cancer you know a lot of people think of it kind of as this dangerous you know mutating disease, and the nature of cancer is also described as a tumor, which is you know very accurate. But today we're kind of looking at the area around that which is called the tumor microenvironment.

Erik: So, what is the tumor microenvironment?

Phillip: Yeah, so that's a great question, and I think a lot of people, including Dr. Rowley, are still trying to figure that out. But it's been well characterized to this point, and that it's a cellular environment, you know that the cancer cell grows in, and it's got a lot of parts to it. So you have you neurons, you have immune cells, and you have your vascular components you know, your blood vessels, that bring the nutrients in there. And these are all pretty normal components of you know normal tissue, but where it becomes the microenvironment of the tumor is that...is that these can change and can react to the tumor itself, which is I think what we're going to hear a lot from Dr. Rowley today.

Brandon: And I remember from class and from some of the labs and stuff I've been in the micro-environment around the tumor is one of the big reasons why the immune system itself isn't able to fight off the cancer cancerous cells. Because this ...isn't it a fairly normal thing for when a cell mutates it becomes too much...too little like itself that the immune cells like macrophages and whatnot can come in and sweep that out, but something about that change in microenvironment allows the tumor cells to persist right?

Phillip: Yes, I think that is a little bit 2-fold... one that the tumor itself changes and that the immune cells don't recognize the tumor as well...you know for face value. That they don't have the same cell markers or they kind of...I think a lot of them down-regulate the normal marker that would present the you know "I'm sick" message that most immune cells kind of look for to take it out. But also the microenvironment has a lot of components that kind of down-regulate the activity of immune cells. So a lot of the current immunotherapies that are making a lot of waves right now in cancer treatment and very effective are targeting these signals that cancer cells produce and kind of build-in in this microenvironment area that interact with the immune cells that are coming in and basically turn them off. And that's one of the ways that the tumor can grow.

Brandon: Yeah, and that's kind of hijacking some of the normal processes around wound repair right? So you've got macrophages, and other immune cells come in, they clean up an area once it's wounded and then you start having a down regulatory response right? So that you can actually start having angiogenesis and then...

Erik: Yeah well so this is something we'll be talking to Dr. Rowley a little bit about, and I think what you're referring to is for...at least for the epithelium is something called the epithelial-mesenchymal transition or EMT, and that's been studied, actually being studied a lot in the case of cancer but historically was studied for development. But basically it is the idea that epithelial cells, you know to give the brief background, your body is made up of three layers, the endothelium, mesenchyme or middle, and then the epithelium. And the epithelial cells during wound or during development or during metastasis will take a mesenchymal state as they migrate, and so they take that when they migrate into a wound, and it's also been linked to maybe what cancer cells do to become systemic and metastasize. So we'll talk about that a little bit but Phillip, would you mind telling us a little bit about the background of...you know this idea that the microenvironment is important and potentially important for cancer?

Phillip: Yeah so when I was doing some research for this episode I came across kind of the first idea of this microenvironment was in 1889 by a paper by Stephen Paget, and he called this the seed and the soil hypothesis. And he noticed you know...he wasn't looking at cell markers, tumor biology, that sort of thing I mean this was...this was a while ago. So he was just noticing that the metastasis of breast cancer was non-random, that it didn't just spread around the body, but it went to certain locations, and so he called this the seed in soil where the cancer cell was a seed, and it grew preferentially in certain soils, certain other tissues that it liked to grow in. And well I don't think he...you know, he wasn't like the founder of the tumor microenvironment, but I think that kind of speaks a little bit to the fact that this has been recognized and can be recognized from a very simple level. That the area that a tumor grows in is also important.

Erik: Cool, well, so looking forward to hearing more about that from Dr. Rowley.

Phillip: Yeah, so, Dr. Rowley is with us today ...he's very kind to do an interview with us for this podcast. And so, Dr. Rowley did his undergraduate and Ph.D. work at the University of Iowa and then did a postdoc here at Baylor. And he's a professor of the Department of Molecular and Cellular Biology and faculty at the Dan L Duncan Comprehensive Cancer Center. His laboratory was the first to identify and characterize reactive stroma myofibroblasts as a key component to the microenvironment in prostate cancer and benign hyperplasia of the prostate. So Dr. Rowley is also a part of the leadership for the Baylor School of Medicine, and he gives many of our fantastic lectures in histology, and immunology, and tumor biology. So we're very happy to have him with us today.

Phillip: Thank you for being with us today, Dr. Rowley. Would you like to start by telling us a little bit about yourself, and how you got to Baylor, and what your position is here?

Dr. Rowley: Yes, as soon as I finished my doctoral training of my Ph.D. I came to Baylor College of Medicine as a postdoctoral fellow in 1980. Worked in a laboratory interested in understanding androgen action, so we studied an androgen receptor in the prostate gland. That led me to an interest in interactions in the prostate gland and prostate cancer interaction between the cells and then stayed on the faculty. Started I believe in 1985 and have been here ever since, in the Molecular and Cellular Biology department.

Erik: How did you decide to come to Baylor? Because for those of us who know you, if I'm not speaking out of turn here, you're from the Midwest, to begin with, and Iowa specifically. I'm from Illinois, and I know like part of me always thought like, I would just stay in Illinois, or Wisconsin, or around that region. But I'm curious what was your calculus that brought you to Baylor?

Dr. Rowley: The cell biology department at the time, which became molecular and cellular biology was really the mecca to go to if you were interested in steroid hormone receptors, under the leadership and work of Dr. Bert O'Malley, as you all know. And so if you were interested in any type of steroid receptor, this was the place to come. And my doctoral work was also in prostate cancer, and so I was interested in androgen receptor, and really one of...Dr. Don Tindall was here as one of the top labs in the United States doing that, and so I came here to do my fellowship research.

Phillip: Most of your work now is in cancer research, and most people are familiar with the idea of cancer growing and mutating and invading tissues. But your work is on the tumor microenvironment, which is the area right around this. Can you kind of describe this environment for us?

Dr. Rowley: Well as its name implies it's the environment that's immediately adjacent to and regional there with cancer foci. They could be primary cancer foci, so in the primary tissues where the cancer arises, and it could also be at sites of distant metastasis where cancers travel to, and form colonies, and grow as metastasis. And essentially the microenvironment have both cellular components as well as non-cellular components. In terms of the adenocarcinomas, which are made up of a cell type called, as you know, epithelial cells...the microenvironment, which is primarily what we study, the major cancers such as prostate cancer, breast cancer, colon cancer, lung cancer, are those types of adenocarcinoma, and the cancer cell is the epithelial cell. So the cells around them are called stromal cells. There's also immune components in the tumor microenvironment, and there are vascular components, and then there are the what's called the extracellular matrix fibers— a lot of different fibers that are produced that help really hold the tissues together. And so these cells are sort of along the ride with the cancer cells, and as cancer cells grow they form a tumor, which is the mass, and in that tumor are the cancer cells plus all of these cells of the tumor microenvironment and fibers. There's also nerves in the tumor microenvironment, so blood vessels, nerves, immune components, and stromal cells, and the fibers that they make, along with all of the other factors, like growth factors and things that they make, means that this microenvironment is a very complicated environment with many cell types. Of course, it varies from site to site, tissue to tissue. The metastatic site is going to be different...probably, than the primary site and the major questions are how does this microenvironment affect cancer initiation, cancer progression, during the natural course of the disease.

Erik: Now you say probably, so does that mean that...I guess it's not quite understood fully whether it actually is different? Are there some cases where the cancer microenvironment is the same?

Dr. Rowley: You mean different between the primary site and the metastatic site?

Erik: Yeah like a normal site, if you will.

Dr. Rowley: Yeah, yeah, the question is how similar are these microenvironments between the different types of cancers, and I don't think that's a...that's a resolved question yet. I still think it's an open question. There are common cell types that are there, but then what makes them different is there's different amounts of stroma, there's different amounts of this microenvironment, there can be some tumors that are say...nearly 100% tumor cells and very little microenvironment cells. There are other tumors, such as pancreatic cancer, where the microenvironment makes up more, most likely more than 50% of the tumor, maybe 70% of the tumor is microenvironment and 10, 15, 20 percent of the tumor are actually the cancer cells. So although common components can be found, the amount of those components and their heterogeneity is different in different cancers, and even within a type of cancer, there can be a lot of heterogeneity between patients. And then even within a particular tumor if we're talking about prostate cancer, there can be heterogeneity in that tumor. So there can be regions of the tumor that are nearly all cancer cells and other regions that have 50% cancer cells and 50% microenvironment cells. The reason for that is essentially unknown.

Phillip: So when you talk about this microenvironment, you consider it part of the tumor?

Dr. Rowley: Yes, yes. And I think that's for many people, of course when we say the word cancer, we focus immediately on the cancer cell, and then when we say tumor if we visualize that many people visualize that as a mass that is essentially all tumor cells, cancer cells. But in actuality, there are a lot of cells in that tumor that are not cancer cells, and the question is how is... how does the biology of those cells affect the tumor? And does it promote the tumor? Is it inhibiting the tumor? Sometimes we tend to think of well...which one is it? And it's probably not one or the other, but the answer is yes, it's both at the same time. There could be some components that are stimulating the cancer cells to proliferate and invade, there are other components that are inhibiting the cancer cells to proliferate and invade, and maybe the question is what is the net effect of those two. Is it pro-tumorigenic or anti-tumorigenic?

Erik: Well I'm curious, so how did you...because most people that get into cancer research want to study the cancer itself, but I know that a lot of your research, as we've already alluded to and have talked about, is about the environment. How did you get into looking at the environment itself?

Dr. Rowley: When I was studying androgen receptor, we were looking at the makeup of the prostate gland and what cells have the receptor. And it's primarily in the epithelial cells, which are making the export product of the androgen reaction in the prostate gland. But there were many very important studies in the '70s and '80s, and particularly in the early 80s, investigators showed that the stromal compartment of cells had a great influence during development on the differentiation, and gene expression, and proliferation of the epithelial compartment. So during development, these compartments of cells co-evolve and develop together, and they greatly influence in a reciprocal manner each other's biology. So then the natural question would be as a tumor forms does this stroma...this microenvironment also affect the growth in the biology of the cancer cells much like it does during development. And so because my work was focused on androgen receptor and prostate cancer, we started thinking more about hey, what about this microenvironment? Might some of the biology that happens during development also be happening during the tumor, and if so is it early in tumorigenesis, sort of a pre-malignant stage? Is it as the tumor is growing and forming, does it promote the progression there? Does it promote invasion of these cells to invade outside the organ and go into a more of a metastasis? And those were all unanswered questions, and in terms of very specific mechanisms, many of these questions remain unanswered.

Erik: And just a quick clarifying, I guess question and statement. By stroma you're referring to like fibroblasts along with the fibers that they're excreting into the environment like collagen and fibrinogen and...whatnot, is that correct or...?

Dr. Rowley: Yes, yeah, the classical terms of tissues are parenchyma and stroma, as you know. The parenchymal was viewed as the cells that perform the major function of that particular organ so if it's a secretory gland-like salivary gland, mammary gland, pancreas, prostate gland, etc., the parenchymal would be the epithelial cells that are under very specific gene regulation to make the export products for that particular gland. And the stroma was considered support tissue. All of the tissue outside of the parenchyma was the stroma, so that means essentially the stroma is that entire tumor microenvironment and it would, as I said immune cells, vascular cells fibroblasts, nerves, they're all an extracellular matrix it's all part of the stroma.

Erik: I understand.

Phillip: So you briefly touched on this in the last couple of statements here, but when we talk about the microenvironment and cancers, cancers themselves have these mutations that are driving their, you know, tumorigenesis and their dangerous aspects...and the microenvironment you're talking about either feeds off this inhibits it or is affected by it. What parts of the microenvironment or maybe what proportion of the microenvironment do you think is driven off the cancer mutation versus kind of an existing biology.

Dr. Rowley: I think that's a great question, and the short answer is we don't have a complete understanding of that yet. I think an attractive way to think of this is that the microenvironment is a normal diploid...meaning no gene mutations happening in that compartment, and that it's following a pattern of almost a tissue repair type pattern, if you will a disruption of the homeostasis of the tissue inducing, you know, an existential repair mechanism. And that this repair process is essentially what happens in this stromal compartment in the tumor. Now the question is if there's specific mutations in the epithelial cells does that tweak or alter the stroma...that stromal response and I don't think we know the answer to that. I don't think a lot of studies have directly in an experimental setting compared a normal wound repair process to the exact same process in a tumor micro-environment. My particular view and bias on this is that that it is much the same. And I think if that is the case it's an attractive hypothesis because that means it's a normal response to an abnormal change in the cell that becomes the cancer cell, and as a normal response if that's true it's predictable what that response is ...it's from a normal diploid cell, and when pathways are more predictable they may be better targets for therapeutics—novel therapeutics or existing therapeutics. There may also be more reliable biomarkers because if that's true that compartment of cells and that biology may be less variable between patient and patient, more predictable, and that may give you a less of a moving target for your therapeutics. Or as the cancer cells are genomically unstable, they're constantly changing, they're evolving into the to the environment, they're becoming therapeutic resistant, and so the therapeutics are a living target. It's not to say that therapeutics to the microenvironment might not do the same thing, so we just don't know that.

Erik: Yeah well if I may, and this is becoming a bit of a mantra I think of questions that I've asked of actually previous people on the podcast too, but would you agree with the statement that maybe some of our misunderstandings about this...the stroma and how much it affects the actual progression of cancer is due to technical limitations of studying it? And I asked this because I did some research on keratinocytes in my past, I would say that was my wheelhouse, and I started trying to look at you know the collagen makeup, and you know the extracellular matrix because it's incredibly important, but it was very difficult. And the stains...you know you can stain for collagen, but you end up having to do it, or at least histologically you know there's preparation that takes place, and you end up maybe losing some stuff. I think there was an NYU paper recently that kind of tried to talk about that it's like the process of histology you could be losing important parts of the extracellular matrix that maybe we're not thinking about. Do you think that's true?

Dr. Rowley: Yes I think it's very much true, it's a good question that the technical limitations of being able to study that compartment of cells and their biology, does that limit our progress? In my view, the answer is absolutely yes. As a good example, we know there are tissue-specific promoters in genes that are specific to those epithelial cells between different tissues because they make different proteins, ergo they have different gene regulation. So we can take a promoter to a gene that is expressing...say a milk protein and target a transgene or a knockout gene to the mammary gland. Or we could take a gene that is androgen-regulated specifically to the prostate gland, and that would target a gene, a new gene, a transgene or a knockout to the epithelial cells. But we do not have tissue-specific, nor necessarily cell-type-specific promoters for many of those stromal type cells. Maybe we do for some of the nerves, and maybe we even do for some of the immune cells, but the fibroblast...and that's a very broad category; fibroblast is a very broad category, a lot of different types of fibroblasts, particularly in this repair tumor microenvironment. We have no good promoters or ways to target gene expression or knockout of genes specifically to that compartment of a subtype of cell. If we did, we could then better dissect the contribution of that cell to the overall biology of the tumor-like we can in epithelial cells.

Erik: Correct me if I'm wrong so...would that mean then like for instance you can't tell a fibroblast that's making type I collagen from one that's making type IV.

Dr. Rowley: Well with immunohistochemistry, you could do that yeah because you could stain the cells for a pre-pro form of the collagen and the ones making collagen I would light up and the ones making college IV would light up with a different antibody.

Erik: But there's not a genetic marker that distinguishes?

Dr. Rowley: I don't know if there is or not, I don't think so. I don't there are, there are some genes that we can you know tell a difference between say a mesenchymal stem cell versus a myofibroblast versus a fibroblast cell type that is... that is not more of a myofibroblast. So we can look at some immunohistochemistry stains and distinguish some of these cells, but it's ...imperfect, and we just don't have the ability to sort of distinguish those cells. At least to the level that we would like.

Phillip: So to switch gears a little bit, so one of my favorite sayings of you, when you lecture to our classes, is that cancer doesn't have a steering committee that decides it wants to promote this angiogenesis or metastasis, a lot of the hallmarks of the dangerous cancer...but these are normal functions of a wound repair and this normal biology we've been talking about today. So can you describe kind of what these dangerous actions of a tumor can be that can be attributed to this microenvironment and this...this biology.

Dr. Rowley: Yeah, it's ...it's a good question, and it's just a natural thing that all of us do, I've done it too, and we try to sort of personify cancer.

Erik: Anthropomorphize?

Dr. Rowley: Anthropomorphize cancer, and it's a natural thing to do I've done it too where we say you know essentially when we're giving our talks we're saying, this is an evil disease. Cancer cells want to kill you. They want to metastasize, they want to do this and want to do that, and at first hand it's ...it's fine, it's helpful. It helps us understand the devastating biology brought forth by this disease, and that's a good thing. On the other hand thinking of cancer that way if we take it too far can lead to the wrong types of questions that are asked in the research laboratory or even in clinical research as to the cancer. And so really when we think of the biology, cancer does not have a steering committee that meets on Monday morning and says, well you know we're a little behind schedule we want to be metastatic here by you know in the next 2-3 months because we would really like this patient to go downhill much more quicker than it...because we're evil and that's what we do. So sometimes cancer biologists are asked for why does cancer metastasize, and you know the answer is well ...that's just kind of what they do. So it changes the kind of questions that you ask. I think that again, in my view, much of the biology of the microenvironment is, and this could be an ironic thing, much of that biology is designed to repair tissue quickly. And if epithelial tissues everywhere, as you know and as you've heard, they are barrier functions, so they separate outside world from inside world. So the luminal side of an epithelial lined gland or the surface of your skin surface of your long service of your GI tract those are all exposed to outside environment, and when that epithelial layer is breached there must be a very rapid...there is a rapid repair mechanism. It's existential; if it doesn't repair rapidly enough, you would have gained access of microorganisms because of that breach, the microorganisms would get in and cause an infection, which could go and...be very serious. So repairing this rapidly is very important. I don't think that stroma that does that rapid repair knows that the defect is a knife wound or a cancer growth. I suspect that the signals that are received basically are communicating that a breach has happened, and a repair process must take place, and it's existential. So that repair process is designed to keep you alive under stress conditions, and if that theory is right that same repair process is what's promoting cancer progression and so if that's the case then the cancer ...it's a normal function that's actually designed to help keep you alive but it's promoting the cancer proliferation, invasion, and perhaps metastasis. Now that's one way of looking, and of course, there are many opinions, this is just my opinion. There are many opinions on this, and the other way of looking at this is that yes, there are different things that cancer cells make that are not made by normal tissues that maybe there is the foundation or the basis of this normal repair process. But because of the extra growth factors or extra other immune-suppressive functions of the cancer cell are somehow tweaking and modifying this response, so that's actually more promoting of the cancer. And in the areas where it might be inhibiting those cancers go away, and physicians never see those, we only see the cancers that progress, the ones that go away we don't know so much about. So one way of looking at cancer is that you're getting cancer possibly a lot and many of them are taken care of and gone away, but the only ones we see clinically or in the research lab are the ones that do survive and exist. The ones that might be more interesting to study are the ones that don't survive, to know why they didn't survive, and we could probably get a lot of clues from that.

Erik: Yeah, well I wonder if this would be a good point to talk about...because you briefly alluded to it before the epithelial-mesenchymal transition and how that ...that's sort of a buzzword that you find a lot in cancer research now. Would you be able to speak a little bit on that and what that is and how it relates to cancer?

Dr. Rowley: Sure, it's the epithelial-mesenchymal transition or EMT...it's used a lot, and it describes the process by which these epithelial cells change their morphological phenotype and their physiological function and start to not look like an epithelial cell and start to invade the tissue much like a mesenchymal cell would. So, therefore, the name epithelial to mesenchymal transition.

Erik: Mesenchymal being, in this case, the fibroblast, which is the stroma?

Dr. Rowley: Right, more like the fibroblast. Now, this is a term that was not... at first, talked about in cancer, it happens in development. So most of your organs, all of your organs that have epithelial cells, these EMT processes happen in development, so this is not a cancer-specific term. Again, it's an open question as to whether this EMT happens in normal wound repair. So if you were to cut yourself with a knife I can tell you that the stromal tissue would start to grow in, the epithelial cells would start to proliferate on the surface of your skin, and they would start to invade across the site where the wound was. Is that EMT? Are the same genes that are turned on in EMT cancer turned on at that site? It's still an unresolved question. I don't think it's been thoroughly studied. Again, my opinion and bias is that it is much the same. I think EMT again is a normal process that's designed to rapidly effect and promote wound repair, which again as I said needs to be rapid. The difference is, if that's the case, the difference is those cells resume their normal polarization, their normal phenotype, as you know if a wound heals correctly the only thing that will be left is a collagen scar— those extracellular matrix fibers scar— and the cells that actually started to form the wound, some of those will go away, the immune components will subside, and the epithelium will have healed all over at the top, and the cells will resume, and that's a process that ostensibly takes place with normal diploid cells. If that same process is now taking place with cancer cells that are no longer diploid, have gene mutations—maybe oncogenes that have been activated or tumor suppressor genes that have been repressed—then that process is off balance. And instead of the cells stopping and polarizing and re-differentiating, they continue to grow and metastasize.

Erik: Yeah...no I think that's a very interesting field now, at least I have interests in that and I also just find it fascinating that...because we grew up kind of thinking okay an epithelial cells is an epithelial and a mesenchymal... is it pronounced mesenchymal I keep saying mesenchymal?

Dr. Rowley: Both works fine.

Erik: Both works, that's good. I don't want to look like an idiot here! But amazing to think that you could have...like they could change, and then this gets therapeutic options open up, and I think that's where a lot of people if people have heard of mesenchymal stem cells, that's a whole field now.

Dr. Rowley: And yeah well, that's a good ...that's a good point and a good question and a good point of clarification. Because in my opinion again, I don't think it's really a conversion to a mesenchymal cell type, it is an epithelial cell still that looks like mesenchymal cell and starts to express some of those genes, but a mesenchymal stem cell can be differentiated to a lot of different types of stromal cells that can be differentiated to smooth muscle, or to bone osteoblasts, or to cartilage chondrocytes, or to an adipocyte. And these cells that have undergone...that were an epithelial cell that have undergone EMT. I don't think it's been shown that they have that multipotentiality. So they're not truly a mesenchymal stem cell. They have mesenchymal properties, and oftentimes there's an MET, where these mesenchymal cells convert back to an epithelial cell. So yes they're mesenchymal in the way they look, but they're not really...and this is another good point because there is a lot of confusion with the terminology here with many of these things too, and you know there's other examples of this kind of terminology that can be can be very confusing.

Erik: I think there was a paper that recently showed that they took an epithelial cell and turned it into an adipocyte, but I could be... I'll have to look that up on the back end.

Dr. Rowley: It...that wouldn't surprise me, and I and I do think we have to keep our minds open, and you know we're learning more and more and more about these...about these processes. But the terminology can be confusing, for example, a cell type in the stroma that's associated with these cancers are appropriately called carcinoma-associated fibroblast. That's been the word that has been used for 20 years or more in the literature, but the problem with that is that it's biased and that's because of its name, it makes you think that it's somehow cancer-specific. Well, how is it possible to have a cell type that has evolved to be just...to serve cancer's role to grow. Doesn't seem to be...to makes sense, and really when you look at those cells, they have pretty much the same gene expression and phenotype as a cell in a wound repair if you cut your skin, or a cell that might be in the wall of a diseased blood vessel by a plaque—might have pretty much the same phenotype. So by calling it a carcinoma-associated fibroblast the people that are studying these cells in a vessel wall and studying them in wound repair might not study them because it's like, no we're looking at a cell type called a myofibroblast. In my view, a myofibroblast and a carcinoma-associated fibroblast is the same cell type. But one field calls it a myofibroblast; another field calls it a carcinoma-associated fibroblast, and it leads to some confusion, and I think that we could probably all learn from each other by looking at these other fields.

Phillip: I think that kind of leads well into my next question for you is....this...this idea of looking at the tumor microenvironment is definitely taking hold recently and becoming more popularized, but how much has this infiltrated the way we treat cancer currently in the clinics? Is this something that's being considered now, or is it something that's kind of coming up and going to change things?

Dr. Rowley: I think that's a really good question. I think that it's beginning to affect the field, probably the biggest change in...at least in my view, in the oncology field is the use of multi modalities in therapeutics and not just relying on one therapeutic. A hallmark of cancer is therapeutic resistance, and it's really...at first I think it's hard to understand that, but actually, it makes perfect sense. You know these cancer cells...biology is really...I mean we could talk for forty hours on this, but the biology of tissues is resilient, and when a pressure is applied they'll change from A to B, and then from B to C and biology finds a way to do that. This is what cancer is doing when a therapeutic is applied, it becomes therapy-resistant, and we say oh darn it. But if we look at biology, bacteria, we know for years we have...this is why we have you know antibiotic-resistant strains of bacteria because you evolve those strains because of overuse of or use of antibiotics. And so biology is going to adapt to the pressure, so whereas a therapeutic may destroy ninety percent, ninety-nine percent of the cancer cells, one to ten percent of the cells leftover are now...because they're leftover, are resistant to that antibiotic, and they grow as another tumor. And we say darn it that cancer is evil. Well, it's not evil, it's just a natural biology, it's a selection pressure. So there's a selection pressure, those cancer cells that are responsive die and those that aren't don't and so the tumor that evolves is no longer responsive to the first therapeutic, and so now that your question is how does the microenvironment affect that and we don't know the answer to that. But I think oncologists, in my view at least, they're more sensitive to this maybe we should not push the cancer to evolve into this before it evolves into this therapeutic resistant. Let's stop that and try something else, or let's try combination therapies, or let's mix things up a little bit, so it's less predictable. And I think lessons and clues can be taken from extinction of certain species on our planet where there's multiple pressures that have caused the extinction, but just one single pressure might not have done it. There may have been biological modifications to deal with that pressure, but multiple pressures do it, and I think if we use sort of those ecological principles to look at cancer, we may start coming...and I'm sure there are people doing that.

Phillip: Yeah and this reminds me of...we're in infectious disease block learning right now in medical school, we talk about treating tuberculosis, and I mean you start that with four medications. Because I mean over years of trying to treat it, they realize that if you start with one, two, even three, and you don't get rid of it a lot of times. So I think even our close friends in the ID department would recommend that as well.

Dr. Rowley: One of the things I think that...I think probably, I think all of us would agree, biology is far more complex than what we thought, and it's never linear, and there's always a plan A, plan B. There's redundancies, we know this, and you know we are in my view there's an awful lot of biology we don't know that we're still learning and...for example, what a nerves do in cancer? We know that nerves are very, very important and we have...there have been some very good papers over the last five-six years on this, but it's still in a field in its infancy. But for sure, for sure nerves affect cancer, but we just do not understand the mechanisms of how that works.

Erik: Well, that leads us in nicely to our second to last question here, so what excites you about you know future discoveries and applications of microenvironment field?

Dr. Rowley: Yeah, you know we're always pushing for better diagnostics and prognostics, and we're always obviously pushing for more therapeutic approaches, and as we talked about in the last question multi modalities of this and multiple therapeutics may be at once. So an overall, overarching goal here might be to say, can there be a diagnostic that we can find from this tumor microenvironment that can help distinguish patients that maybe need—in diseases such as prostate cancer—more of a watchful waiting, versus those that should be treated more aggressively sooner rather than later? And then in terms of the treatment might there be a way to target the tumor microenvironment, in other words targeting the niche of the cancer so at the same time you're targeting the cancer cell, so a double-barrelled approach: One at the niche that the cancer still lives in, one at the cancer cell. And then maybe even having several options for both of those compartments. I really think to control cancer...I don't know that cancer will ever be eradicated because as long as genes mutate, it's going to be hard to eradicate it. I think there's a lot of progress on that for a lot of reasons, but I think for treating it and controlling it this multi-pronged approach...and you know if you look at species that have left our planet, unfortunately, it's because their niche has been destroyed. And so if we take that same principle towards cancer, destroying their niche, not allowing them to start growing in the first place, or not allowing them to metastasize, or by somehow uncoupling the important biology that is ...that's synergistic interactive biology with the niche. If you can uncouple that I think that's a very powerful approach, and that's the rationale that we use in many of our research proposals as to why we think understanding these compartments, and really understanding things like general wound repair. It's incredibly complex, incredibly complex, and we still...we know the cell types that are involved, but we don't know necessarily all of the factors that regulated it, how those factors are integrated, the signaling pathways inside the cells. How do the cells, if you have a hundred different cell types doing wound repair at once, how do they all coordinate themselves so that everything happens in the right coordinate manner, so you end up with a perfect repair with a minor scar? How does that happen? We don't really know.

Erik: Well and the fact that you don't regenerate hair follicles, right? Am I wrong in saying that?

Dr. Rowley: Yeah as humans we...you know compared to lower organisms, we really don't regenerate. We repair our tissues, we don't necessarily regenerate our tissues, unlike lower organisms such as Planaria. Where you cut the head off a Planaria it grows a whole new head back; there's only one stem cell in a Planaria. We have a lot of different stem cells and rather than go to the complex process of regrowth of a new organ we would repair that organ much with this type of microenvironment repair type tissues. It's what happens in cardiac infarction. When the cardiac muscle dies, it's replaced by this fibrous repair tissue, it's not replaced by normal cardiac muscle, as you know. So if we were able to regenerate it would be a lot easier just to have that system just grow back a new heart tissue, right? But it doesn't necessarily happen. That's why we end up with scars when we were cut, the collagen stays, and it's not exactly normal, but it's pretty close.

Phillip: Yeah, I really like how you take that ecological niches is very interesting. I think for our final question today, just as one of our great lecturers in the medical school, I think talking a little bit about your teaching style is a little bit...unique, and would be a fun topic. A lot of times you talk about a design criteria that, you know, a bone needs to meet, and then we go into the histology and cell types of that. Would you like to talk a little bit about that?

Dr. Rowley: Yeah, yeah, sure. I guess I started this many, many years ago because I found it when I was learning all of this I just couldn't sit...well, I could, but it wasn't fun. I just couldn't sit down and memorize things for the sake of memorizing. A good way to learn is to understand the story of how something works. And you know you can try to memorize all the components of something, but if you understand how components go together and how they work with each other, pretty soon you end up knowing exactly how it works and what they do and it's a story of how it works. And so rather than give a lecture where we say, here's a list of things that we need to memorize for today because trust me you'll need to know this to practice medicine or to do your scientific research, or be a good medical educator, and our medical students do all three of those areas. So a better way to do this is to say, if you are designing bone how might you design it given that you need...these are the design requirements: Bone must be lightweight but must be strong, it must have an ability to be hardened, but those same ions can be used in blood chemistry—calcium and phosphate. How would you design it? Given...you've got some cells, you've got some fibers, and you've got some glue. How would you put it together, and sometimes I ask are there engineers that have looked at carbon-fiber technology and fiberglass and things like that? It's fibers, glues, and hardeners. It goes back to an Adobe. Mud, straw, and water. Okay, they harden, and it's an adobe brick, and if the wall is thick enough, they can last for hundreds and hundreds of years. If you don't put straw in it, it falls apart immediately at the first storm. So the fibers are important. So we go through all of those concepts, and the students learn how...if they are designing bone if there's a design concept. You know-how is an immune system, how would you design an immune system if you needed it to do A, B, C, D, E, and F? How would you design a blood vessel if you needed it to do this on the arterial side versus return blood to the heart on the venous side? You wouldn't put valves on this side, but you might put valves on this side. And so it makes more sense, it makes more sense to understand it from if you were making it how would you make it, and you can kind of have fun with questions like that.

Erik: Absolutely yeah, well speaking of fun this has been a blast. Thank you so much for taking the time to talk with us and again we really appreciate also all your lectures. They have been helpful, and I agree completely that being able to logic out something is a lot away to memorize it than just you know, getting the little parts so...thank you so much.

Phillip: Thank you.

Dr. Rowley: Thank you very much, thank you for those comments, and it's been my pleasure, thank you.

Erik: Alright, that is it for now, we would like to thank everyone out there who took the time to listen to this episode of the podcast. Special thanks to Phillip for writing the episode. Thank you to our faculty advisor Dr. Poythress for helping us put everything together. Thank you to the Baylor communications department for help with the production and website, and thank you again to Dr. Rowley for taking the time to be interviewed with us. We hope everyone enjoyed it and hope you tune in again soon, goodbye for now.