Cancer I Flashcards

Question

Sarcoma

Answer 1

arise from connective tissue or muscle cells.

Answer 2

Each cell, when it divides, generates two identical new ones. So, when a cell acquires a mutation, it passes that mutation on to its progeny during cell growth and division. Because cells with cancer-linked mutations tend to proliferate more than normal cells, cellular candidates for additional mutations grow in number. Mutations continue to accumulate and are copied to descendant cells. If one cell finally acquires enough mutations to become cancerous, subsequent cancer cells will be derived from that one single transformed cell. So all tumors are clonal, which means that they originate from a single parent cell, whether that first mutant cell was of germline or somatic origin. - Tumors are clonal --> That is they start from a normal cell which acquires a mutation - If there is only a single mutation then that cell may continue to divide and only carry that single mutation. - Cancer doesn’t arise from a single mutation! Cancer cells acquire multiple mutations and as they begin to acquire mutation things don’t go bad right away - There is a critical point in which the cancer cells will create “cancer” - Cancers don’t arise from one single mutation, they acquire multiple mutations. And as they acquire mutations, they don’t necessarily go bad. - Clonal simply means that they share a common ancestor - Such an example is seen with the philadelphia chromosome in which all the tumor cells had this mutation in common, showing that they all came from this. One thing to keep in mind is that although cancers are clonal in nature, they are heterogeneous, meaning they are different from tumor cells on the other side of the tumor generally.

Answer 3

-It takes a long time for a tumor to show up because it has to undergo many cell divisions in order for the cancer cells to accumulate. -10^9 cells the tumor becomes palpable 10^12 cells, it generated death -Tumor cell has to undergo massive amounts of cell division which gives it an advantage but it takes a long time

Answer 4

Genomic instability in cancers. As cells age, they decrease the expression of telomerase and increase the expression of p53, which leads to irreversible senescence. In cancer cells, there is often a loss of p53, allowing fro mutant cells to continue to proliferate. This leads to a condition where chromosomes fuse then break-resulting in chromosome loss and translocations. Telomerase is reactivated in some of these cells leading to stabilization of the aberrant chromosomes and continued proliferation. - Lets start by looking at a normal endothelium cell which undergoes repeated cell division. - So what happens in many normal cells is that telomeres shorten and eventually uncap which leads to p53 cell cycle control and senescence which means the cells undergo an irreversible stage of shutting down and stop dividing - The loss of p53 though allows the cells to grow and proliferate. Because they lack p53 they can continue to divide and cant fix all the mutations that are occurring, thus acquiring different mutations which is referred to as chromosome breakage fusion-bridge cycle. - JUST KNOW THAT YOU UNDERGO A PROCESS OF ADDITIONAL CHROMOSOME BREAKAGES WHICH LEAD TO CHROMOSOMAL INSTABILITY - If the damage is too severe, in some cases the cell will die. - In some cancers, telomerase is reactivated and now the cancer cells can continue to divide and keep the chromosomes. - High expression of telomerase leads to immortality -Just know that p53 has a role in chromosome instability and p53 plays an important role in this. Also know that telomerase allows these cancer cells to survive even with unstable chromosome due to the upregulation of telomerase

Answer 5

Transformed cells (grown in culture) are abnormal in shape, motility, responses to growth factors, and loss of contact inhibition. This loss of contact inhibition leads to this rounding up of cancer cells because they no longer associate with their neighboring cells

Answer 6

- One of the ways that cancer cells do continued growth and division is through an altered metabolism. - Normally cells have a very low metabolic rate when they have stopped dividing. - In nonproliferating cells, O2 is present and glucose is converted to pyruvate in glycolysis. Then the pyruvate mainly goes to oxidative phosphorylation to generate energy, CO2 and H2O. Only a limited amount goes to form lactate.  THIS IS OXIDATIVE PHOSPHORYLATION -In a cancer cell though, or in early development and highly proliferating tissues, a slightly different process occurs because of the massive intake of glucose. The glucose is converted to pyruvate in glycolysis but only a small fraction of pyruvate is shunted into oxidative phosphorylation! Majority goes to form lactate. You need the cell to produce more and more molecules, energy, building blocks in order for the cell to continue to proliferate. WANT TO PRODUCE THE BUILDING BLOCKS NECESSARY FOR CELL GROWTH!!! - This is known at the Warburg Effect where cancer cells undergo this aerobic glycolysis and convert massive amounts of glucose to lactate. - This was postulated in 1974 and Warburg said that this was the main cause of cancer, that these cells will have defective mitochondria and as a result will use this process instead but Warburg wasn’t really correct. This lactate process just seems to take over but the other process still occurs. - If the cancer cell shuts down the mitochondria, it will block the intrinsic pathway of apoptosis. Now there are drugs being tested that reactivate the mitochondria to reactivate the mitochondria to reactivate apoptosis - Normally cells have a low metabolic rate - In a cancer cell or in highly proliferating tissue, the glucose uptake is massive. Also, a vast amount of the product goes into lactate. Converts glucose to lactate. - The oxidative phosphorylation process still occurs in the mitochondria -Just know it occurs in cancer cells and it is an effect on metabolism that gives cancer cells an advantage by creating building blocks. Lactate will be broken down to make other things

Answer 7

Three-step hypothesis for tumor cell invasion across basement membrane. Receptors on the surface of tumor cells bind to laminin protein in basement membrane. This induces the secretion of pro-collagenases and other proteolytic enzymes (i.e., uPA or urokinase plasminogen activator), which degrades the collagen and other proteins of the basement membrane. Tumor cell then migrates through the dissolved region of the matrix. The reiteration of the process leads to the invasion of the metastasizing tumor cell through the extracellular matrix and basement membranes in metastasis Non-transformed endothelial cells in angiogenesis invade by a similar mechanism. To invade through basement membrane, cell expresses the protease enzymes procollagenases and urokinase plasminogen activator (uPA). uPA activates plasminogen (expressed by liver and ubiquitously located in the extra-cellular matrix (ECM)). uPA activates the plasminogen in extracellular matrix by hydrolyzing a central peptide bond that gives the active protease enzyme plasmin. Plasmin will degrade the ECM directly and also activate procollagenase to collagenase. The collagenase is specific to type IV collagen of basement membranes. - Part of the way it does this is because the tumor cells have a lamin receptor and they bind to lamin which is on the basal lamina. Then the tumor cells release a collagenase which can allow it to break through the basal lamina and allow the cell to move through it. - In this case, the tumor cells themselves are secreting the enzyme necessary to break through the basal lamina beginning with receptors on the basal lamina - They need laminin receptors

Answer 8

The cells will undergo a EMT shift via the TGF-beta and Wnt (Epithelial to Mesenchymal shift) to become more de-differentiated and this will allow the cells to metastasize. Then, once they reach a new location, they undergo and MET shift to become more differentiated again Progression from normal epithelium to invasive carcinoma goes through several stages. The invasive carcinoma stage involves epithelial cells losing their polarity and detaching from the basement membrane. The composition of the basement membrane also changes, altering cell-ECM interactions and signaling networks. The next step involves EMT and an angiogenic switch, facilitating the malignant phase of tumor growth. Progression from this stage to metastatic cancer also involves EMTs, enabling cancer cells to enter the circulation and exit the blood stream at a remote site, where they may form micro- and macro-metastases, which may involve METs and thus a reversion to an epithelial phenotype. - Primary cancers occur in the normal epithelial and lose their contact inhibition as well as by the extracellular matrix and basal lamina. - They acquire metastatic properties by undergoing EMT  They actually change their whole program of gene expression and allows them to escape their normal barriers. The subset of cells in a tumor that metastasize go through an epithelial to mesenchymal state transition. In the mesenchymal state the cell acquires a stem-like de-differentiated phenotype. In order to colonize its target tissue the metastatic cell reverses its phenotype by transitioning back to a more differentiated epithelial state. EMT, epithelial to mesenchyme transition; MET, mesenchyme to epithelial transition. - How do cancer cells undergo these transitions from being benign to metastatic? - There is actually a physical process that has to occur  EMT (epithelial to mesenchymal transition) - Cancer cells start in an endothelial state and undergo EMT which takes them from a more differentiated state to a less differentiated state (mesochymal) - This allows the cells to get more motility Cells lose E-cadherin in their plasma membrane  loss of the ability to form adheren junctions Cells lose cell-cell and ECM contacts, round-up, and acquire a motility. They activate a series of kinases or kinase cascades. Activation of PI3K/AKT and classical RAS/MAPK pathways. Pluripotent transcription factors activated which give the cancer cells the ability to de-differentiate and allow the cells to acquire a more stem cell like state (Slug, Snail, Twist, Nanog, FoxC2 , Myc). Increased protease secretions (urokinase plasminogen activator and type IV procollagenase) coupled with decreased protease inhibitor and extracellular matrix secretions. 2 Points: They undergo the EMT transition. They undergo the reverse process once they get to their new location! MET occurs then! These cells have the ability to undergo both!!! - They are becoming less differentiated via EMT - TGFB and Wnt stimulate EMT to get epithelial state to mesenchymal state

Answer 9

1) Activate or maintain telomerase: Telomeres do not shorten during cell growth 2) Inactivate p53 to block senescence: p53, when activated, is a pro-apoptotic response which creates BH3-only proteins.

Answer 10

Metastasis accounts for 90% of cancer associated deaths. Metastasis is a multi-step process involving invasion of local tissues, movement through the circulation, leaving the vessels, establishing new cellular colonies at distant sites. Only a small portion of invasive cancer cells can function as founders of metastases (less than one in one million cells). - This is the process of metastasis - There is an initial growth of a benign tumor in the epithelial cells and they continue to divide - At some point they acquire invasive properties and invade the capillaries - Now they can move throughout they body. - At a certain point, they can adhere to blood vessel walls in the body and then they can escape from the blood vessel to form a micrometastasis - Where the tumor began in one part of the body, it has now moved and invaded somewhere else and is now in a new microenvironment and can form a second tumor in a different location Studies of labeled tumor cells leaving a tumor site, entering the circulation, and establishing metastases show which steps in the metastatic process, outlined in Figure 20–16, are difficult or “inefficient,” in the sense that they are steps in which large numbers of cells fail and are lost. It is in these difficult steps that cells from highly metastatic tumors are observed to have much greater success than cells from a nonmetastatic source. It seems that the ability to escape from the parent tissue, and an ability to survive and grow in the foreign tissue, are key properties that cells must acquire to become metastatic. (Adapted from A.F. Chambers et al., Breast Cancer Res. 2:400–407, 2000. With permission from BioMed Central Ltd.) - In considering the whole process of metastasis, it is not a simple process - There are easy parts and hard parts - Only about 1 in 1,000,000 cancer cells that invade can go one to form and metastasize at another place. But it only takes a couple of cells to do this! - Out of all of the cells it doesn’t take that many to go out and metastasize. - It is difficult for the cancer cells to invade the blood vessels  They have to acquire the ability to secrete these molecules in order to invade the barriers that hold the cells where they are. That is a difficult process to occur which is why it typically takes a while to see metastasis occur. - However, once they get into the blood vessels or lymphatic system they can survival pretty well and exit in a new location easily because they already have these enzymes and such. This is easy to do - Once they get to the new site though, it is not easy to form a new microcolony! They first have to be able to survive in the foreign tissue which is not as clear cut. And they have to begin to grow and form microcolonies and then invade the normal constraints of growth in the new location

Answer 11

In both cases, the cell secretes uPA (urokinase plasmingen activator) which will cleave the plasminogen to plasmin which can then degrade the ECM and also cleave procollagenase to collagenase.

Answer 12

Tumor cells express Fibroblast Growth Factor (FGF) and Vascular Endothelial Growth Factor (VEGF) which cause endothelial vascular cells to increase expression of proteases and inhibit expression of protease inhibitors. This assists in the invasion process.

Cancer I Flashcards

(36 cards)