Osler 1

Meghan Osler Instructor: Malcolm Campbell English 1103 11/2/12

Looking on the Bright Side of Cancer Pink, squishy, and inert, a whole human kidney rests in the hands of Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine. The crowd erupts in applause as Atala presents this life altering medical miracle. Behind Atala is a 3D printer which uses a cell layering technique to produce another kidney just like the one he holds in his hands. In the next ten years organs like this will help diminish organ donor lists and also allow patients who receive transplants to live healthier lives. Unlike donated orangs, these are created using the recipients own kidney stem cells and virtually eliminates the risk of organ rejection (Atala). Since we live on a planet with an ever increasing population, the demand for organs will increase as well. The work Atala does at Wake Forest is of the utmost importance to the health of the human race. In these modern times you would have to do some serious searching to find a scientist who would deny that stem cells are taking an essential role in medicine and biological research. That being said, you would also have a great amount of difficulty finding a scientist who didnt believe that cancer is awful disease which kills millions each year. While seeming like polar opposites, stem cells and cancer cells have much more in common than most people would think. They share physical and physiological properties which blur the lines between the so called good and evil with which the two have been labeled. These similarities not only change the way we should look at cancer as a whole but also in the ways we treat it in the clinical setting. As

Osler 2

research and analysis of these similarities continue I believe the medical community will drift away from the notion of curing cancer and toward the prospect of controlling cancer instead. Covering the Basics The National Institute of Health defines stem cells as undifferentiated cells which can renew themselves through cellular division. Through specific induced conditions the cells can take on the properties of specific organs or tissues, a process called differentiation (National Institutes of Health). These cells are found all over the body and are responsible for the diversity of its tissues and organs. Stem cells can also be divided into two separate categories, embryonic and somatic (adult) stem cells. Embryonic stem cells are found within embryos while somatic stem cells are located within tissues and organs in the adult body. Embryonic stem cells occur in developing embryos and when the cells become specialized they form all the tissues and organs found in the body. These types of cells can only be found in embryos, placenta, and umbilical cord blood. The primary job of a somatic stem cell is to repair old or damaged tissues in the body. These somatic stem cells are only partially differentiated and can only produce more cells within a specific tissue. A single organ may also contain several types of somatic stem cells. Bone marrow contains two known stem cell types. One type, called hematopoietic stem cells, are responsible for the formation of blood cells in the human body. The second type called bone marrow stromal stem cells produce bone, fat, and cartilage cells. Both cells have been used in regenerative therapies for over fifty years (National Institutes of Health). Since that time stem cells have been discovered in virtually every area of the body including the heart and brain. These cells have also shown promise in the fields of regenerative medicine and organogenesis. In areas like the brain, where stem cells are scarce, illness can be

Osler 3

especially devastating. The lack of stem cells means that the body will be less able to recover from traumatic events than other areas of the body. Scientists are using embryonic stem cells to treat affected areas and regenerate masses of cells which have been damaged due to injury or diseases such as Duchenne's muscular dystrophy (National Institutes of Health). The potential of stem cell based therapies seems almost limitless and stem cells are becoming more widely accepted as viable treatments in the scientific community. Stem cells can help eliminate frightening and deadly diseases in the same way that vaccines have in the past. We still dont understand stem cells enough to say for certain what they can or cant do, but they have the potential to permanently alter the way we look at and treat disease. How Can Cancer Fit in this Model? While the scientific community has known about stem cells for quite some time, their potential relationship to cancer is a more recent development. While not all scientists accept the idea of cancer cells, most agree that there is more to cancer than genetic mutations. In an article by Suling Liu, Hasan Korkaya, and Max S. Wicha called Are Stem Cells Ready for Primetime, they explain that the majority of cancers actually come from cancer stem cells (CSC), which as their name suggests, behave in a very similar way to normal stem cells. Cancer stem cells have the ability to self-renew and produce more malignant cells, while also being able to differentiate into the cells which produce the bulk of the tumor. Cancer stem cells were first seen in leukemia. When leukemia cancer cells were transmitted from and infected mouse to a healthy one only certain sets of cells actually caused cancer. This showed that only certain cells were responsible for the production of tumors and these cells were deemed CSCs. In areas where solid tumors grow it is much more difficult to identify the cell types and determine which cells cause cancer without damaging or altering the tumor (Suling, Korkaya, and Wicha 34).

Osler 4

Since stem cells and CSCs behave in almost identical ways, it becomes clear that CSCs must somehow arise from normal stem cells. The division of undifferentiated stem cells could be one of the CSC sources. Arabinda Nayak from the Atmiya Institute of Pharmacy states that stem cells have an extended lifespan due to their ability to replicate and remain undifferentiated which gives the cells more time to build up the mutations that occur during cell division. Through mutations, the cell division becomes irregular and eventually CSCs form. In his paper Involvement of Stem Cell in Cancers, he asserts that CSCs may also arise from differentiated cells that acquire the ability to dedifferentiate into a stem cell like state. Mutations within the differentiated cells would cause the dedifferentiation of these cells. Large cell populations in a tissue increase the probability of mutation in the differentiated cells and offer more chances for CSCs to arise (Nayak 3297). It seems that cancer stem cells do arise from normal stem cells, but only if the stem cell populations are quite high. When the body is injured it will respond by increasing the production of stem cells to heal the damaged areas. This would then increase the likelihood of stem cell mutations and the productions of CSCs. This could explain why tissues damaged with poison or chemicals are even more likely to develop cancer. Not only do the chemicals alter the DNA of differentiated cells but they also damage surrounding tissue which would elicit an increase in stem cell populations. However the CSCs only become an issue when they divide and begin to produce tumors. Understanding the growth and reproduction of these tumors would give insight into why these mutations occur and how it may be possible to stop or control them. Cancer Stem Cell Involvement in Cancer Current models of cancer life cycles and growth include a process called metastasis. Nayak explains that metastasis occurs when cancer spreads from its origin and travels to a new

Osler 5

area of the body. These cancer cells often travel around the body through either the blood stream or lymphatic fluid. When the cells begin to grow in a new location they form metastatic colonies (Nayak 3297-3298). While CSCs do differentiate to form the bulk of tumors they also may be able to adopt phenotypes that allow epithelial-to-mesenchymal transition (EMT). In this process the stem cells drop their tissue like properties and obtain the ability to travel to other locations. Once they the CSCs have found a suitable area they start to differentiate again to form tumors in the new location. Inflammatory immune responses and hypoxia have both been shown to induce EMT responses in CSCs (Suling, Korkaya, and Wicha 34). This time we find that the reasons behind cancer metastasis are inflammatory responses and hypoxia which is a lack of oxygen to the tumor itself. So when the body is injured the body sends out stem cells to heal the area. But the more extreme the injury the more likely it is that CSCs will develop. These CSCs then move from area to area depending on where the body sends out stress signals. If the initial stem cell responses produced by the body could be better understood or controlled then all of the CSCs could be used to their ultimate healing potential. Controlling Chemical Signals The goal of conventional cancer therapies like radiation and chemotherapy is to attack solid tumors to hopefully kill off the tumors cells. These therapies however do not account for CSCs. Tannishtha Reya, Sean J. Morrison, Michael F. Clarke, and Irving L. Weissman work for the Departments of Pathology and Developmental Biology at the Stanford University School of Medicine. Using combined efforts they authored an article called Stem cells, Cancer, and Cancer Stem Cells which sheds light on the mysterious world of CSCs and their role in tumor development. When the typical cancer therapy destroys tumor cells the CSCs remain. They can then generate more CSCs which will differentiate into more tumor cells. They believe that new

Osler 6

cancer treatments should focus on attacking the CSCs themselves. Specifically attacking the CSCs could lead to the destruction of metastatic cancer cells and even cancer cures (Reya, Morrison, Clarke, Weissman, and Irving L 110). The defensive behavior exhibited by CSCs is quite similar to that of a stem cell population responding to an injured or diseased tissue. Considering how similar CSCs are physiologically to stem cells it is possible that cancer type responses are intentional but just uncontrolled. If instead of becoming tumors CSCs could become correctly organized tissues they would become keys in restoring areas which have received extensive damage. But because these massive stem cell responses are not genetically stable they can become cancerous and damage the body instead of healing it. It is no secret that organelles within a cell communicate with each other as well as with the wall of the cell. Mina Bissell, a respected and distinguished scientist who runs Bissell Lab in Berkeley California, has devoted her life to examining how cells communicate with their environment and how deficits in this communication attribute to cancer growth. In one experiment she observed that cells implanted with cancer genes would produce tumors growths in a laboratory dish, which is an expected result. But when the cells were injected into a chicken embryo the cells remained noncancerous. She also conducted an experiment where she removed mammary cells from a mouse and placed them in a dish. The displaced cells no would no longer function properly and lost their typically cellular arrangement. When Bissell returned the cells to the mouses body they started to function and produce milk. These results made Bissell think that cellular context was one of the key factors to cellular function. In a third experiment mammary cells which were placed in a dish with some of the extracellular matrix (cushioning which surrounds the cells) and this time the cells functioned the same way they would if they were in

Osler 7

the mouse. Bissell hypothesized that cellular functioning is not only regulated by the surrounding structure but also with how the cells send and receive signals from the surrounding cells (Bissell). Bissells experiments show that cancer genes may not be the only factor that regulates the growth of cancer. If for some reason stem cells lose the ability to signal with the extracellular matrix then the cells will mutate and become CSCs. An increase in stem cell population would increase the signals received and sent to the extracellular matrix. It is possible that this would cause confusion among the cells and possibly turn on the cancer genes inside of them. If it were possible to help the body regulate these signals then massive stem cell responses to injury would do their intended job instead of potentially becoming cancerous. It is also possible that increase in stem cell populations would stress the extracellular matrix and interrupt the signals that it sends to the stem cells. Where Can These Discoveries Lead Us? There is overwhelming evidences for the benefits of stem cells and stem cell therapies. They can be used to cure disease, grow organs for transplants, and treat damaged tissues which would otherwise not heal. I can think of no reason why anyone would ever want to eliminate these amazing cells. That being said, actually wanting to eliminate cancer is a questionable idea. If cancer is actually an extended stem cell response to extreme injury, then it would be best to understand what actually goes wrong when this response occurs. Increased cellular signaling, delicate genes, and miscommunication with the extracellular matrix play a role in CSC development. These are all systems which we do not completely understand. While no one would argue that we shouldnt find new ways to treat cancer, we should also continue to research what actually causes cancer.

Osler 8

As medicine quickly advances it is highly likely that we will find ways to control stem cell signals to allow them to function without losing control. However this would be a highly complex process and would ultimately require years of laboratory testing. For this new view of cancer to be correct we would need to understand why certain injuries result in cancer and others dont. We would also need to know why certain organs or tissues appear to be more resistant to cancerous growth when injured. As it is now, no one should celebrate cancers existence. But we should consider its true purpose and its usefulness in our precious bodies.

Works Cited

Osler 9

Atala, Anthony. Printing a Human Kidney TEDMed. 2011. Web. 11 Nov. 2012. Bissell, Mina. Experiments that Point to a New Understanding of Cancer. TEDGlobal. 2012. Web. 15 Oct. 2012. Liu, Suling, Hasan Korkaya, Max S Wicha. "Are Cancer Stem Cells Ready For Prime Time?" Scientist 26.4 (2012): 32. MasterFILE Complete. Web. 4 Nov. 2012. Nayak, Arabinda. "Involvement of Stem Cell in Cancers." Journal of Pharmacy Research 4.10 (2011): 3295-3299. Academic Search Complete. Web. 5 Nov. 2012. Reya, TannishthaMorrison, Sean J.Clarke, Michael F.Weissman, Irving L. "Stem Cells, Cancer, And Cancer Stem Cells." Nature 414.6859 (2001): 105. MasterFILE Complete. Web. 5 Nov. 2012. "Stem Cell Basics." Stem Cell Information. The National Institutes of Health, 28 Apr. 2009. Web. 6 Nov. 2012.