I wanted to be a pediatric oncologist by the time I was in middle school. My interest sparked by the movie “6-weeks” and an endless obsession with movies focused on sick children. Later, I discovered a fascination in cancer biology: the tumor’s ability to sustain its own growth, travel to distant sites and actively evade treatment. Despite this passion and being a cancer trifecta (cancer survivor/patient, cancer doctor, and cancer horoscope sign); I am no world’s expert in tumor biology. I always preferred scientific pontificating more then being a lab researcher. Hopefully I can still teach you a couple things about cancer biology. This is not a scientific text; it will attempt to make the complex simple and is limited to my own understanding; all of which may result in some inaccuracies. Please feel free to post follow up questions, self-study, or pose questions to your oncologist.
When I was first studying cancer biology, I was taught that tumors were collections of identical cells that developed errors in DNA (Changes in gene sequence called mutations) which enabled the cells to sustain growth and spread. Cancer biology in my college biology 101 course focused on the cancer cell and on two types of cancer causing mutations. One was mutations of tumor suppressor genes that in healthy cells can halt cell division. When these genes are “turned off” (cell stops making functioning protein), the cell loses a critical check point on cell replication important for preventing uncontrolled tumor growth. The other was mutations that “turned on” oncogenes. Oncogenes stimulate cell replication and turning on these genes can lead to tumor growth. It was understood that multiple mutations were needed to form a cancer and that cells with mutations are more susceptible to developing new mutations. Not surprisingly, tumor biology is more complex, and with each passing year tumor biologist make discoveries that add additional layers of complexities. Two review articles that do an excellent job at defining 21st century cancer biology were published by authors Douglas Hanahan and Robert Weinberg in the journal Cell[1;2]. I will do my best to summarize using some of my own conceptualization to try to explain to non-biologists non-oncologists. But for those interested in a deeper understanding, read these papers. My goal is to provide understanding of some of the complexities of tumor biology as a framework to understand therapy. In future post I want to be able to discuss what distinguishes targeted therapy from chemotherapy and the concept of “personalized” medicine. I would like to help you with the language and understanding to generate discussions with your doctor about clinical trials and molecular profiling.
- A new image of cancer.
- No longer do I picture cancer as a collection of identical cancer cells, but instead I picture a unique organ. Tumors are complex structures composed of cancer cells that are not all identical as well as blood vessels, blood/immune cells, structure composed of both cellular and non-cellular parts. There are subpopulations of cancer cells that may differ in functional properties such as capacity to initiate and sustain growth as well as differ in the environments where they thrive. Environment can refer to different organs and/or different exposures (hi/low oxygen, rich/poor nutrient, presence/absence of chemotherapy). Cancer cells can sometimes masquerade as other cell types. The different cells within the tumor influence one another. Moreover, there is a cooperative effort amongst the different cells to promote survival, cell division and spread. Because a property of cancer cells is that once they have a few key mutations they become more able then normal cells to develop further alterations. This means they are adaptable and change over time. If you think about evolution and understand how genetic events can be influenced by outside factors one can understand that changes in tumors can be influenced by treatment. Meaning the genetics and properties of a relapsed cancer may differ sometimes substantially from the cancer initially diagnosed prior to treatment.
- Cancer is a genetic disease but that does not mean it came from mom or pop
- Cancer is a genetic disease. Less commonly in cancer, this means that you have inherited a gene from mom or pop (germline mutations). Such cases do occur, examples include cancer susceptibility syndromes such as (Hereditary Breast and Ovarian Can (BRCA1/2), Familial Adenomatous Polyposis). More often cancer is caused by acquired genetic changes, meaning mutations occur in previously healthy cells (somatic mutations). Sometimes gene alterations can be influenced by environmental factors (smoking, Chernobyl) but more often it is something that just happens. We have subpopulations of cells in our organs that are dividing over our lifetime as part of health maintenance. When cells divide our entire genetic code, over 3 billion nucleotides (the base unit of DNA), must be copied. Despite our bodies AMAZING capacity to double and triple check this process, mistakes occur. Furthermore, other types of events can occur in these cells. Where sometimes I am frustrated with media coverage of environmental factors, because I am concerned about inaccuracies, especially when they are misunderstood, place blame, and make a patient feel guilty about their cancer. Recently, I was excited to see the media highlighted a recent article by Bert Voglestein and Cristian Tomasetti earlier this month in the Journal Science. This article mathematically explains the frequency of cancers in particular organs as being correlated to the number of cell divisions expected for that organ over time. The headlines read “cancer patients just have bad luck”. Personally, I think people who do not get cancer just have good luck.
- To be more complete when I describe cancer as a genetic disease, I mean changes in cells are due to alterations in gene expression. Gene expression meaning the genes in coding part of DNA that are transcribed into RNA and then translated into a protein that has some functional role to the cell. I do not mean always mean a mutation (an alteration in DNA sequence). Today we understand that the both genetic and epigenetics can result in changes of gene expression and functional alterations in cells. There can be alterations to DNA that effect gene expression that are not sequence based but are chemical changes such as methylation and/or acetylation. There can be DNA alterations outside of the coding region where the genes reside that result in alterations in micro-RNA that can alter gene expression. There can be actual chemical changes (methylation, farnesylation, ubquitization, lipodation) of proteins referred to as posttranslational changes. Some of these are consequences of the changes in genes. Furthermore, it is not only our nuclear DNA that can be altered. Nuclear DNA is typically what we think about when we are discussing are DNA (DNA organized into 23 pairs (1 from mom and 1 from dad in form of chromosomes and is found in the cell nucleus) but there are other types of DNA (mitochondrial DNA) that may have changes. Sometimes it is not the quality of the gene (sequence) but the dose or amount of a gene present. This is particularly true of some genes that control cell division such as oncogenes. Some genes have their dose (copy number) controlled by chemicals changes mentioned above make it so only one of the pair of genes is translated. Sometimes this is done in such a way that it is specifically the mother’s gene or the father’s gene that is not translated, this is called imprinting. Some cancers have a loss of this imprinting, so that both genes contribute and therefore the gene is present in a higher than normal dose. For cancers where genetic predisposition exists sometimes it may be because only one of the pair of genes has a mutation. In such cases our healthy cells may not be effected because we also have a normal copy of the gene. When an error happens in these cells and the normal gene no longer contribute and cancer develops, this is called loss of heterozogositiy. To summarize this paragraph, the genetics of cancer are variable and complicated.
- The Hallmarks of Cancer Biology (Not all of these are distinct entities but overlapping)
- “Turning on” signals that promote cell division (oncogenes)
- Our bodies tightly regulate the division of healthy cells present in our organs. They cannot sustain their own division. These cells take cues from their surroundings.
- By “turning on” oncogenes, cancer cells may regulate, initiate, and sustain their own division by stimulating certain pathways. Some of the pathways are Ras GTPases, MYC, RAF, Tyrosine Kinases, MAP kinases, mTOR kinase. You may hear about these pathways and others because they can be targets of targeted therapy.
- Our bodies tightly regulate the division of healthy cells present in our organs. They cannot sustain their own division. These cells take cues from their surroundings.
- “Turning on” signals that promote cell division (oncogenes)
- “Turning off” tumor suppressors
- Normal cells senses stress (low sugar, low oxygen, DNA damage) in their environment and can shut down cell division. Turning off these genes allows cancer cells to divide when a healthy cell would not.
- “Turning on” signals to spread to distant sites which occurs in steps
- Healthy cells have growth stopped by its surrounding (cells &non-cells) referred to as contact inhibition. Healthy cells that are part of an organ also have specialization (limited functions) and internal organization (cell polarity). Such features help normal cells have purpose and placement within an organ which help regulate its division. Metastasis occurs when a cancer cell disassociates from their surrounding in the original organ of origin (Primary tumor), crosses borders, and take residence in new distant organs. This process involves many steps. The cancer cell goes rogue: end its dependence on surrounding healthy cells and disassociate from the organ. In carcinomas this process is called EMT (epithelial-meschymal transition). They may develop new functions (via changes in the cellular proteins) such as motility and ways to alter their environment so to clear their path. They need to gain the ability to enter a route of spread such as the blood or lymph vessels (intrasavation). They also need to be able to exit into distant organs (extrasavation). This process may be random, the cell may be “invited”, or they may choose which organs to go to. Not all cells in that are present in the blood will be capable of metastasis. Once cells are in a new organ to develop metastasis (changing from micro-metastasis to macro-metatasis) they need to grow in a new environment. Not all arriving cells may be capable of initiating this growth but only a small subpopulation. Timing of growth may or may not be orchestrated by the primary tumor. The genes expressed in the cells in metastasis may vary from those genes in the primary tumor and in metastasis in other organs. Cells may be pre-programed for this role, they may change into this role, or there maybe changes in the new environment that allow this growth to start. The seeding of the “right” cells may actively recruit other cells. Subpopulations of these cells may also go and join other cells that are residents of other organs or return to the primary tumor. This means the more spread to different organs the more potential for even more tumor cell diversity and changes over time.
- How does it even make sense that a cancer cell can develop all these different new functions? Although these different functions may sound different they are often linked. Have you ever heard you oncologist call your cancer or pre-cancer “immature cells”? One way these different functions of cancers cells are linked is that they are actually normally activated together during growth of embryos. During this early development we change from a clump of similar cells into cells able to detach, move, reorganize, divide, take on new functions, and set-up in new tissues. So cancer cells turn-on pathways that are present during development and therefore look “immature”. This is why many of the important discoveries in cancer biology and medicine actually come from the study of normal human biology. This is a reason it is imperative that we not only fund cancer directed research but also basic biology research.
- Becoming immortal
- The meaning of “immortality” here is that cancer cells have an unlimited potential to undergo divisions. Healthy cells have a finite number of cells divisions. Immortality may also be a characteristic limited to specific subpopulations (cancer stem cells) most critical for initiating, reinitiating, and sustaining cell growth. Potential to replicate is partly determined by telomeres which are a repeating sequence found at the ends of chromosomes. As healthy cells they often reduce their telomere lengths, reducing their future capacity to divide. Early tumor formation is often accompanied by telomere loss, reflecting the divisions. Once a cell has reached it replicative potential and cannot divide again it either is destine for death or a non-proliferative state (cell senescence). One way some cancer cells accomplish immortality is through turning on a way that they can reconstruct these telomeres.
- Getting a blood supply
- The “angiogenetic switch” made NY times headlines when I was in medical school in the late 1990’s (http://www.nytimes.com/1998/05/03/us/hope-lab-special-report-cautious-awe-greets-drugs-that-eradicate-tumors-mice.html). The initial concept was cancers start to grow and then there rapid growth causes them to lose their blood supply, losing their access to oxygen and nutrients, and therefore they need to “turn on” genes that allow them to recruitment new blood vessels. This was the angiogenetic switch. It made sense that if we could prevent this switch then we could stop cancer growth. This became and still is an important target of targeted therapy. But this alone is not the cure to all cancers and the story has become more complicated. Cancer cells seem to find a way to take advantage of bad situations and use them for their benefit. So this stress state instead of causing death may drive the growth of a small population of cancer cells that have their genes altered to survive such conditions. Again the cancer evolves over time and this maybe partly driven by events in the cancers cells surroundings. So the subpopulation of cells that survive may establish cancer and it may be genetically different from the first cancer cells that were growing. This is also something that comes from developmental biology. A common way for cells to alter their gene expression and to know something different needs to happen is by losing access to oxygen.
- But it is still holds true that many cancers do “turn-on” this angiogenetic switch and many cancer cells still require blood supply. This may be a bulk of the cancer cells making up the tumor. Not only is this important for the growth of tumor but also is an important part of allowing for growth of metastasis. This maybe one way the primary tumor can exert control over changes at distant sites.
- Additionally, it is now understood that blood vessels produced by tumors are not the same as normal vessels: usually they are disorganized leaky pipes. This can cause leakage of into the tumor space making the tumor more rigid and swollen. Such an environment would stress a healthy cell but this again drives gene expression changes in cancer cells. It can also create pressure on the normal vessels and make drugs less able penetrate the tumor which they need to do in order to work.
- This is not really proven but has been my conjecture and shown to be true at least in some cases. I think in some difficult to treat cancers, it may not be enough to target the cancer cells but also the tumor environment. To me it makes sense that that when the target is the cancer cell the main goal should be death of cell. Not that in some rare cases returning it to a normal state may work. But when I think of the surrounding cells I think that returning those cells to normal makes sense. This is often the goal now for therapies that target blood vessel formation. Whereas previously the goal was using these at doses to block new vessel formation, now treatment plans use these drugs at lower doses causing normalization of the blood vessels and can be used to aid delivery of drugs that are targeting the cancer cell. Designing therapies to normalize function is not easy.
- Staying alive: avoiding death
- There are multiple biological types of cell death: Apoptosis when a cell receives a programed cell death signal, the cells shrinks, the DNA is fragmented, and then the cells dies breaks apart and cleared by neighboring cells but does not damage nearby cells. This is often triggered by chemotherapy. Autophagy: this is a biological process that is in response to specific stressors that can both promote cell survival via a cell “hibernation” or cell death. In this process the cell uses derives energy from its own components. Necrosis: Although previously thought “bystander” death now it is recognized that there is it can be either programed or un-programed. Either way death happens because of damage to cell membranes by internal or external factors and the cell swells, there can be spillage of contents and damage to surrounding cells. This can occur in central tumors that have outgrown blood supply and can sometimes occur with chemotherapy.
- In healthy cells, a good response to stress, especially DNA damage, is to activate cell death (apoptosis) so that don’t have the growth and division of an unhealthy (pre-cancerous cell). Cancer cells may develop mechanisms to stop this death process and survive, and therefore are able to accumulate more and more damage and changes. Loss of the tumor suppressor TP53 is typical in many types of cancers. Other mechanisms cancer cells develop involve turning on proteins that act to prevent apoptosis such as bcl-2.
- Cancers like viruses take advantage our remarkable human biology and make it work for them. When cells are damaged and undergo necrosis, inflammatory cells are called to clean up the debris. In the presence of these cells in the tumor environment can promote survival to the tumor cells.
- New targeted therapies try to block cancer cells avoidance of death. Medications that try to reduce toxicity of chemotherapies to healthy tissue sometimes try to take advantage of the fact of the different responses of stress of healthy tissue and cancer so that what may have a protective effect on normal tissues may not affect the tumor.
- Changing dependence on energy (oxygen and nutrients)
- Autophagy is cellular response to stress such as oxygen and nutrients and can be a pro-survival mode, where the cell is hibernating, not proliferating, and is dormant or can lead to cell death. Tumors as they grow quickly can outgrow their blood supply causing a low oxygen, low nutrient environment. Therapies can also cause similar stress. Activation of autophagy can be a way for the cancer cells to survive. But in other cases can result in cell death. Cancer cells need to shift this to pro-survival mode. Understanding this balance to help make other therapies more effective is currently being studied.
- Impact of the tumor environment: 2 way sword
- Tumor cells can develop a relationship with the immune cells and other cells in the tumor environment that promote survival and at the same time can avoid other cells such as immune cells that are targeting their destruction or other cells and non-cells that send growth inhibitory signals.
- Inflammation has a complex relationship with cancer. On one hand there are inflammatory disorders and viruses that through extended periods of chronic inflammation can predispose to cancer. The role of inflammation in general is to repair tissue that has been damaged, so one can imagine that part of tissue repair is cell replication and recruitment of blood vessels which are also things that tumors do. On the other hand our immune response is also important for preventing cancer. There are immune disorders where you do not have normal functioning immune cells that predispose to cancers.
- In the blood you have red cells that carry oxygen, platelets that help repair vessels to quickly stop bleeding, and white blood cells that are the immune cells. There are many different types of immune cells, neutrophils that fight bacteria and lymphocytes that fight virus. The lymphocytes that are important for prevention of cancer include cytotoxic T-cells. These cells also fight viruses. These cells recognize virus infected cells, because viruses have genetic material that when it infects a human cell use that cell machinery to make proteins from the viruses’ genetic material. The cytotoxic T-cell sees these proteins because they are not present in healthy cells and it knows the signature of a healthy cell. Likewise, it also notices changes in gene expression caused by the cancer because it differs from healthy cells. Cancers that arise in patients with abnormal immune systems can differ then cancers in patients with normal immune systems. Cancer in the present of normal cells has to be good at evading the immune cells, whereas cancers that arise in the immunocompromised do not need share this feature. This is why when possible restoring the immune system can be an important part of the treatment in such patients. Another type of lymphocyte that can destroy tumor cells is natural killer cells. These cells kill stressed cells including cancer cells. Having an immune system that can kill your tumor cells is also part of the rational for bone marrow transplantation. Bone marrow transplantation not only allow the patient to get higher doses of chemotherapy because they do not have to worry if the doses destroy the blood system because they will get a new blood system, but the infusion of immune cells also have a direct effect on destroying the tumor which in some cases can be more effective because it comes from a different person. Capitalizing on the immune system has been a part of cancer therapy for a long time, but more recently new strategies are being developed to rid the cancer of the mechanisms they use to hide from the immune system.
- There are other non-cancer cells and even non-cellular parts of the tumor environment besides from immune cells that can also negative and positively impact cancer. There are cells are promote metastasis by providing “piggy backs” for cancer cells to get across vessels. There are cells that provide the tumor cells with the growth signals.
- Instability of the Cancer Genome
- Our bodies are constantly protecting us from developing cancers. Our bodies have developed multiple ways to prevent mutations but cancers once they developed and have one or two mutations are predisposed to accumulating more. One reason is that cancers are caused by mutations that promote replication, and with each replication the possibility of an additional error is present. Some of the genes commonly mutated in cancers, called caretaker genes, are actually responsible for checking the DNA is copy correctly. Some of the chemical changes that I discussed above can affect the dosage (copy number) of multiple genes. If you getting a test of the DNA sometimes they are just looking at the sequence which looks for mutations or errors in the gene and sometimes they are looking at the dose level such as CGH (comparative genomic hybridization). Today there are ways of doing both at the entirety of our DNA. Of the multiple changes that may be present not all have the same significance. Some gene alteration are critical to tumor initiation and development, some changes may alter the biology of the tumor but not so critical that they would sustain cancer growth, and other alterations may be purely bystander changes and are not significant to the biology of the tumor. Being able to identify the changes in the tumor cell and understanding the significance of each change is complex research.
- Special cancer cells (cancer stem cells or cancer initiating cells).
- It may only be a small subpopulation of cancer cells that can actually reestablish tumors at relapse or in new sites. It may be that these cells are unique or maybe just in a unique state and the properties of cancer cells can vary by influences from the tumor environment. This small population of cells is sometimes referred to as cancer stem cells. Properties associated with this subpopulation include ability to reestablish tumor growth, replication that can produce both identical and more functionally limited cells. They may be immortal. They also may have special properties like increased ability to protect itself from toxic drugs such as chemotherapy and may express a protein that can dump out multiple types of medications.
- Other factors
- I only told a small fraction of the story based on the limits of my own understanding and ability to put into non-scientific terms. This was not easy so I published prior to perfection. As you can gather all the above impacts how we treat cancer. My goal was to highlight the complexity of cancer. When we move on to discuss therapy, it is even more complicated. Variations in tumor biology are not the only reasons we see varied responses to therapy but there are other factors that impact response to cancer therapy. Some medications that we use may not be directly toxic but require the body to process to have the desired effect. This means can treatment response can also be altered by how our bodies metabolize certain therapies.
1 Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. cell 2011;144:646-674.
2 Hanahan D, Weinberg RA: The hallmarks of cancer. cell 2000;100:57-70.
3 Tomasetti C, Vogelstein B: Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2015;347:78-81.
4 Hanahan D, Coussens LM: Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer cell 2012;21:309-322.