okay so overall so far what we have seen then uh let's summarize what we've done so far in the vcal steam model of cancer so so far if this is the colonic epithelium here what has happened so far is let me just draw the epithelial cell's lower boundary is a single epithelial cell here let's say this is a single epithelial cell firstly it was unlucky enough to suffer a double mutation where it lost function in both of its APC genes so it lost the function of both of its APC genes so aenimus polyposis coli completely
lost function that caused the cell to overd divide so the cell started overd dividing because beta cenum wasn't being destroyed anymore and beta Kenan caused the cell to overd divide so here we go these now are all genetically identical copies of that original cell that was unfortunate enough to get a double hit in the APC Gene and now they're all dividing far too rapidly at the moment though it's quite a small little tumor you've got there and it's not cancerous because uh in order to be cancer what it has to be doing it has is
it has to be invading the healthy tissue and destroying it it has to be horrible basically it has to be invasive and destructive this is not invasive and destructive this is just loads of cells dividing basically and forming a loop uh well sorry forming a um mass in the Lumen of the um intestine okay so this is what is known as an early adenoma now basically what happens next is one of these cells so let's say this one here which I haven't cuted in yet is on one of these cells in the early adenoma so
all of them have this double mutation in APC see now one of them is unlucky enough to get a gain of function mutation in one of its um in one of its um Kass genes basically okay so because you've got a large population of these uh cells which now have uh this double mutation in APC it becomes likely that one of them will suffer another mutation and what happens is that one of them just happens to suffer a gain of function mutation in K so I will now color this cell in Pink So this pink
cell let's outline the mutations it has so in the pink cell this well this purple cell actually it's that's that color uh in this purple cell you now have the double hit on the APC where you've lost function in both of them and now you've got one gain of function mutation in this KRA Gene so this cell now has quite a few mutation in these important genes now APC lot of function in APC that was already meaning that this cell was going to be dividing too quickly now it's got a gain of functioning K as
well so it's going to divide even more quickly than these green cells basically so it's going to start dividing and dividing and dividing and dividing and dividing and dividing and dividing and dividing and before long you're going to have a whole population of cells which are genetic identical to it which all have both uh two loss of function mutations in APC genes and also a gain of function mutation in the K Gene okay so all of these purple cells here now have all of those mutations so they um are um one step further than these
green cells and now we can begin to see the concept of uh intratumor heterogenity which is a really important Concept in uh cancer biology so this is intratumor heterogenity and I'll keep coming back to this as the video progresses uh this is the concept that if you look at the different cells within this tumor some of them will have they will all have different mutations basically and some of them will be further along the progression towards becoming cancerous than others so if I was to take a biopsy of this tumor I might get some of
these green cells which would only have uh two loss of function mutations in ABC and I might get some of these pink cells or purple cells which have both two loss of function mutations in APC and one gain of function mutation in K so that concept that there are these different cells within a tumor which have different levels of mutations and are at different stages of the cancer development process that's known as intratumor Renity okay so once you've got um a um tumor that has both these initial cells which have these double hit to their
APC Gene and also uh the uh gain of function mutation in its K Gene that is then known as an intermediate adenoma so now it's progressed from being an early adenoma to being an intermediate adenoma okay right and it will grow substantially in this process of moving from an intermediate sorry from a early adenoma to an intermediate adenoma okay so the next process then so I want to stress actually that the number of these pink cells is going to very quickly be much larger than the number of green cells basically because these pink cells are
dividing at a rate much faster than the green cells basically so you'll end up up with a lot more pink cells than you will green cells now the next stage is for one of these pink cells which has which all have two knockout mutations in APC and a gain of function mutation in one of the Kash genes one of those is now going to undergo a further mutation and basically what is going to lose is it's going to get lots of function lots of function in both of its smell four genes so loss of function
in smad four okay so I need to now talk to you about uh what smad 4 is what pathway it's involved in which is the uh transforming growth factor beta pathway and then why getting a loss of function mutation in both of those smad four genes is going to then lead to um lead to further uh increases in the rate of which you are proliferating basic basically okay but we'll do that in the next video
