MBG Cancer Biology and Metastasis Transcript Part 1 PDF

So the last piece that I wanna hit before is we're gonna get into the specific cancer biology or cancer genetics piece when we come back. That I will record. But this is all about the basics of what is cancer. Which I know you have a definition of, but we're gonna delve in a little bit deeper. And s...

So the last piece that I wanna hit before is we're gonna get into the specific cancer biology or cancer genetics piece when we come back. That I will record. But this is all about the basics of what is cancer. Which I know you have a definition of, but we're gonna delve in a little bit deeper. And so first and foremost, we have these four principles. To be cancer, to be cancerous, to fit that definition of the big C, if you will, you must exhibit malignancy. That is the difference between a benign growth and cancer. You must have altered heritability from a cellular perspective, not necessarily from an organismal one. The cells must be capable of passing down the altered state. And you must be capable of that genomic instability that causes those changes. Autonomous growth. You are not hyperplastic if you have to be told to grow. You're still responding to that signal. And you have to be able to invade and interfere. And what this means from a 3D architecture of a tissue, if you're an epithelial cell and you have your basement membrane down here, you're going to grow into it. This can be confusing when you think about a ductal carcinoma or a, sorry, or colon cancer, because you're essentially filling in a duct first and that can feel like, okay, well that's invading into the duct. No, it's the surface of the duct. It's this part growing into filling a solid opening. It's invasion around the duct, going this way out into the actual architecture of the duct. That is the invasive piece. Does it make sense? And it also helps to explain why filling in a tube or cancer from the epithelial lining of a tube makes sense because the hyperplastic growth there has room and can fill in that structure before it can disrupt fully. Does that make sense? So most of our cancers are what we call carcinomas. They are going to be of epithelial cells. We do have 10% that are leukemias or lymphomas. And we also have sarcomas, which are gonna be your muscle, your connective tissue, your bone. Most cancers are sporadic and somatic. The mutations are acquired over a lifetime and occur with no evidence of familial history that we can see. No inherited predisposition. Is it possible to have a de novo germline mutation that you got, you're new, and you're the first case in your family? Yes. But then there would be evidence of whole systemic changes in you that would imply that inherited form. We are talking about conditions where if we were to test a tumor versus other cells of the patient, we would see a different pattern. Truly sporadic cancers are not affecting every cell in the body. They are not found with genetic changes observed in every cell in the body. They are truly sporadic. We do have to always add the caveat of no known familial history. Because do we have everybody's family history? Does everybody know everyone they're related to and whether there's, no. And so we do add that caveat of it is possible that it's not a de novo and that there is a family history and it's not truly sporadic. We also don't know every gene that could be contributing to every cancer type. But family history for a true familial inherited cancer is going to include rare and unusual cancers, is going to include a higher incidence of cancer and is going to include earlier onset. Any of those three or any combination of those three would be expected for an inherited or familial cancer. So for this, it's just a reminder using our lovely little colon cancer pie, familial risk only makes up 10 to 30% of the cases. And then we get very specific hereditary syndromes making up smaller and smaller pieces. The majority are sporadic cancers. And this is true for most cancer types. So what is a cancer cell? It's an abnormal cell. The normal processes of regulation are altered. And of course, we're gonna talk about CDKs here. What do CDKs do? They're all about regulating the cell cycle. We increase their activity to drive forward. We decrease their activity to get us to stop, right? Okay, dysregulating CDK activity is a great way to allow a cell to go forward without needing the same rules. What do we specifically block or create to control the CDK? Cyclins. So you can imagine with something that is as complicated as CDK signaling that we actually have multiple hits we can have to lead to the same place, dysregulated growth. This is showing you how we go from early normal epithelium to a metastatic colorectal polyp. What you should see is that each of those stages, each of the progressive places on the path toward cancer involves another change. Whether it's an activity level change, a specific genetic change, something is happening. There is a progressive series of steps. The average cancer takes four to seven unique events to actually be cancerous. So change in one gene that gave you the ability to grow. Change in another gene that would have stopped you from growing. Change in P53 is super common to prevent apoptosis. Turning on telomerase to allow telomeres to be lengthened and maintained so you don't trigger senescence. Common changes in cancers. And now you have metastatic potential. What your first event is is very tissue dependent. Yeah, it's variable. So in the absence of environmental, sorry, repeating the question, how much time would that take to occur? And so my answer was it's variable. Depending on the level of exposure to environmental carcinogens, the potential growth levels, whether you have significant hyperplasia and then dysplasia, whether you have an environment where you're causing multiple additional genetic changes like radiation exposure, lots of carcinogenic food since this is a colon cancer example, it can take years between events. Some events can occur very rapidly. If you have a predisposition toward cancer, the events can happen at an earlier younger age. Hence the cancers in the family history that are diagnosed at younger ages. So you can see that these are specific changes that have been observed. And you can see that we have hyperplasia and then we have dysplasia occurring and we have growth. I think it is essential that we are very clear about the difference between benign and malignant. Malignancy equals cancer. Malignancy doesn't necessarily require metastasis. Not all things that can invade will fully metastasize, but there are key things associated with malignancy that are important to note. Invasive potential, the ability to disrupt three-dimensional hierarchical structure of a tissue is a key component of malignancy. Most of the cells in a malignant form, they're gonna be that de-differentiated, super plastic, able to move, not behaving like they're supposed to be highly observable in H and E staining as being different than what they should. Structurally, physically, behaviorally different. Most benign growths, even when they are relatively large, they were relatively slow growing usually. The cells making up that growth will typically be fully, if not terminally differentiated. There's just been a lot more of them. A lot of times we consider these to be curable, right? Surgery alone is often enough to remove a benign growth, whereas most cancers require aggressive and often multi-factorial interventions. So it is important that we draw that line. Benign does not mean not causing a problem. Have any of you seen some of those news reports of people that have allowed a benign growth to reach excessive sizes to the point where the vasculature becomes a problem? Ignoring symptoms, so even though it's benign, it's causing headaches, it's causing pain, benign does not mean asymptomatic or problem-free. Just means not cancer, not malignant. Malignancy is a multi-tiered process. You start out normal, and then there's an event that changes you. We call that initiation. Something happens that makes you different. It's an exposure. It's a secondary mutation to one you inherited. Something is different. And suddenly you are either able to grow more or you don't look the way you should. Increased growth, hyperplasia. Do not have the appearance and function you should have, dysplasia. They go hand in hand. But they are two different events. You can be hyperplastic without being dysplastic. You can be dysplastic without being hyperplastic. But both are typically necessary to cause cancer. When it comes to these two, they are collectively heading us toward anaplasticity. This is a truly abnormal cell that has gained new potential. It can move. It can tell other things to do other things, right? If you're an epithelial cell, you might be telling a keratinocyte or a fibroblast or an immune cell to do something different. You are now providing instruction that is affecting others. This will lead to the ability to actually disrupt three-dimensional structures and invade into the basement membrane. You have gained that potential. That is a truly anaplastic cell. From there, you have the potential to metastasize. And so when it comes to what we're talking about here, this is normal, right? What do you see? Maintenance of organization, right? There's clear layering. Everything looks nice and organized. We have different material here from here because we're creating those layers. But what about with hyperplasia? We suddenly have more in there, but we still kind of look the same, right? We still maintained some sort of appearance, but check out dysplasia. Do we still look okay? Do we still look the same? Do we still have that structure we should expect to see? No. And if you combine those and you start piling more cells in there and you disrupt surrounding tissues, well, now you have invasion and cancer. So you'll notice that when it came to these, this layer wasn't affected yet. It was always this layer under here being affected. Now with cancer, we have that disruption of this setup. Does everybody see that? That's invasion. In general, from it, yeah, it can be. So initiation can be caused by somatic mutation. It can also be caused by a miscommunication that a cell doesn't respond to in the way that it should. So that's the tissue organizational field theory where the idea is that I've got a conversation I'm not participating in correctly. That can be due to inherited change, but both go together, right? I can develop changes. I can inherit changes and throw off the conversation as a result. Does that make sense? So yeah, no, no, you're fine. Initiation is the first step. Initiation can lead to a potential for hyperplasia, for a potential for dysplasia. It can cause you to just be sitting there going, I don't think this is right. And if nothing else happens, you're fine. If nothing happens to you beyond that first event, it's not gonna cause cancer. In fact, from initiation and promotion, which is truly, we are headed toward cancer development. We have hyperplasia, we have mild dysplasia. These early events are reversible. If we suddenly have a different conversation, we get deleted, we have additional mutation that says, no, no, no, no, no, go back to the way you were, then we're done. We can be reversed and we can be fine again. But once we actually progress, once we become anaplastic, once we become affecting neighboring cells and really creating differences in the tissue, we can't go back. Yeah, no, we're gonna get to staging in a second. So this is what I would, the lead into this was, this isn't, what I'm talking about here isn't necessarily cancer staging. Cancer staging is going to be determined by where we're at in terms of the growth, depending on the cancer we're talking about. For example, renal carcinoma, stage two is very different than breast and ovarian stage two. The concept here is the cells themselves. If we're within the tissue and we have just undergone a few changes, that's considered reversible. We can go back to the way we were. Obviously, that's gonna take external motivation, something happening within the system, intervention, but we don't catch cancer at that stage because it's not enough to detect. We don't catch cancer until promotion and beyond. Even our best diagnostic tools require at least 10 to the eighth cells to detect. That is a really small size. And 10 to the 10th to 10 to the 12th is lethal. So that staging concept is really more about the tumor. This is about generating that tumor. So what are the things we are actually doing? We're subverting norms. A norm is I am this type of cell, I stay in this box to carry out this job. I don't know why there was lots of hand motions to that, but okay. If I am supposed to stay as a single layer, any deviation of that single layer is going to be disrupting. I should not need to have signals to grow if I'm cancer. Norm is I am told to grow, cancer is I don't care what you tell me, I'm gonna do what I want. Part of a I don't care what you tell me, I'm gonna do what I want, comes from our neighbors. We are all sitting near people. Some of us have chairs between. Would we like it if our neighbor just took over our space? So there's some signals you put out that say, you stay there, I stay here, right? This is my space, this is my box. You go over there. Cancer doesn't care. Cancer is not gonna listen to the contact inhibition, the neighbor telling me, okay, you're touching me now? No, you don't grow anymore where we're supposed to be. Cancer's like, nope, I like your spot, I want it. And takes it. Normal cells have a balance between life and death. We grow exactly how much we're supposed to, we get rid of what we're not. Cancer doesn't care. Cancer will keep a cell around that was supposed to die as long as it wants. Cancer will keep growing even when it's told not to. And that's the connection to that last piece. I ignore the signals that tell me to do something else. And so this is just an example of that disruption through e-cadherin. Signals that tell me, this is what I'm supposed to look like. I am not supposed to grow in this way. That's my neighbor, this is where I stop. And cancer just goes, I don't care what you think. And does what it wants. Metastasis is a carefully orchestrated process. Cancer can't do whatever it wants unless it has changes that let it do that. Metastasis includes some of those changes. And so these 10 steps are all necessary for cancer to actually grow in a new location. You cannot get metastasis without adherence. You have to adhere, invade the basement membrane, travel through that material, get to a blood vessel, enter the blood vessel, intravasation, pop along in the blood vessel highway, land somewhere, get out of the blood vessel, move back through the basement membrane, land in the new tissue and grow. That takes a ton of signals and a ton of changes. And one of the most profound changes we observe is on the vasculature. You make the vessels more permeable so you can slip through them. The tumor itself sends signals to promote this. And it will promote niches or places to grow that are highly specific to the cancer. And so I know we didn't get as far in this as I wanted, but I wanted to finish this one little piece and I will let you go for today and I will pre-record everything else. Staging is highly specific to each cancer and is all about the size of the tumor or materials or tissues involved, whether you've affected the basement membrane or not, and whether you've metastasized. But each cancer type has its own staging system from the comparison of whether or not we have actually invaded surrounding tissues. So with that note, I will come back to this in my recording because this is the piece we were supposed to do today. Questions or concerns? Happy Thanksgiving. Thank you for coming. Everything for the rest of the semester will be pre-recorded and available to you so that we can literally just practice, practice, practice for three days when you get back. Sound good? Thank you so much for coming.