Origin and Evolution of Neoplastic Cells: Overview

00:00 Hey, welcome back. We're going to move on from where we have been talking about the biology of neoplasia, of cancer, and get into how that cancer actually interacts with the human body that it happens to be within and that's where we're going to have pathology.

00:20 Just by a very quick review because you've definitely watched and totally memorized and internalized all the previous lectures that you've seen, I'm just going to review real quick. So how does a good cell go bad? So, keep in mind normal cells, all of us are constantly being bombarded by chemicals, radiation, viruses, and things that are potentially carcinogenic. They're carcinogenic or mutagenic because they cause DNA damage.

00:45 Fortunately because we have evolved to recognize that we're going to have DNA damage, we have really good mechanisms to prevent that and most of the time when there is injury to a cell, breakage of DNA, or substitution of different nucleotides we recognize that and repair it. But sometimes for a variety of reasons, that's not successful. And maybe that we just have too much damage. The cells are just, there are too many breaks in the DNA to sufficiently repair it or there are just too many mutations or we have defects in our ability to do that repair and we've talked about germline mutations, the Li-Fraumeni syndrome where there's p53 mutations, things like that. So, there will be additional inherited mutations not only affecting DNA repair but also affecting how well a cell will undergo apoptosis if it gets too messed up. If there's too much DNA damage, cells will usually try to commit suicide but we may lose that ability in a cell going bad. So if we don't have good DNA repair and we don't have the way to keep the cells from progressing even after they have accumulated mutations then we've got somatic cells that have cemented, have locked in particular changes that are potentially deleterious. So the mutations in the somatic cells can be activating growth promoting oncogenes. We've talked about that.

02:13 And so RAS mutations, just as an example. You can also have inactivation of tumor suppressor genes, things like p53 and RB, and together those 2 will lead to an upregulated cell proliferation. Again, at this point, still not necessarily cancer but now we have relatively uncontrolled growth. At the same time, we'd lose the ability to kills cells or have cells commit suicide when they are too deranged. And so now you're not getting adequate killing of mutated cells. That decreased apoptosis and the upregulated cellular proliferation is going to give us a clonal expansion. We're right there, we're right on the edge of becoming malignant, but there are additional changes that have to happen in order for tumors to do their evil bidding. In this clonal expansion, additional mutations are happening so we are having proliferation in the setting where we're not able to do sufficient repair or sufficient apoptosis and basically we are building in more genetic instability. New genes are being activated, new genes are being turned on all the time because of this kind of clonal instability, genetic instability. And some of the things we'll have is we get androgenesis. Keep in mind if a tumor rose beyond a certain size beyond 100 to 200 microns, nutrition oxygen cannot get into the middle of that mass unless the tumors also induce new blood vessel growth in. So, tumors have to reactivate androgenesis in them as it's going to to be successful. And they also have to escape from immunity. The immune system recognizes them of being foreign, they're making all kinds of mutated proteins. Damn.

04:03 If we're going to be successful as a tumor, you've got to learn how to turn down that particular response. And we'll talk more about that. In any event, these things are happening, we get tumor progression and finally malignancy. It's got all the features necessary including genetic instability to be malignant and then the coup de grace finally the tumor can invade and metastasize. Okay. So that's how a good cell goes bad and also how tumors interact with their hosts.