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jubei33
10th February 11, 01:29 AM
First and foremost, cancer is a disease of broken genes. For as long as medicine has existed, cancer has defied our attempts to cure it. It is estimated that one in 3 people will experience cancer in their life time(1 (http://en.wikipedia.org/wiki/Cancer)). More so, "greater than 60 years ago there were no treatments for children with leukemia that could cause remission of the disease, but today this is possible in about 96% of cases!"(2) Though we have made leaps in our understanding and treatment of cancer, the golden fleece: freedom from this oldest plague of man has long eluded us. Perhaps some day we will achieve this ultimate prize, but it seems for the time being we must be satisfied with our current progress. Here's a few reasons why the beast still stalks us:

1. Biological Immortality and unlimited growth:

To keep cells fit and in good working order, ordinary cells are limited by how many times they can divide. This is known as the Hayflick limit (http://en.wikipedia.org/wiki/Hayflick_limit). A cell's DNA has a non-coding region at the end of the strand called the telomere (http://en.wikipedia.org/wiki/Telomeres), which can be likened to a docking station for the DNA replication machinery. Every time the strands are copied this machinery takes a small piece of the telomere leaving behind a smaller and smaller piece. Once the telomere runs out, the cell enters senescence, stops cell division and dies. Somatic cells have about 50 divisions in them before this happens.

In cancer cells, an enzyme called telomerase (http://en.wikipedia.org/wiki/Telomerase_reverse_transcriptase) actively replaces these lost pieces of telomeres, allowing them to divide beyond the Hayflick limit and evade the natural cell death program. Normally, this limitation keeps a cell line's genetic package healthy and mutations from accumulating. However, for cancer cells this is not a problem, as the mutations sometimes serve to provide a survival advantage over normal cells. The tumor suppressing genes Rb1 and TP53, for example, are known to have roles in controlling cell growth, but once they are damaged or turned off they allow a cell to break free of the systemic growth of normal cells.

Retinoblastoma protein (Rb) (http://en.wikipedia.org/wiki/Retinoblastoma_protein), the protein produced by the Rb gene, does its work by prohibiting a cell with damaged DNA from replicating. When this situation occurs, it binds and blocks the transcriptional machinery in cells, keeping it from copying the genome and consequently, proceeding into the next stage of cell division. Many cancer cells have mutations to this gene. In fact, the protein produced by this gene was discovered in a kind of eye cancer called retinoblastoma. This should not be misconstrued as only affecting the eyes, however, as it is a significant regulatory protein in almost every cell in the body.

P-53ís (http://en.wikipedia.org/wiki/P53) main job is to protect the genome from mutation. It acts as a watchdog right before cell division, making sure that the DNA has been faithfully reproduced. If there is DNA damage, then P-53 can stop the cell cycle and activate DNA repair proteins that can hopefully fix the damage. If the damage is too extensive to repair, then it can also signal apoptosis (http://en.wikipedia.org/wiki/Apoptosis), the cell's death program. Without this protein functioning properly, the risk of developing cancer is increased greatly. More so, "greater than 50% of all human cancers contain a deletion or mutation of the TP53 gene" (3 (http://en.wikipedia.org/wiki/P53)).

Mutations of these genes generally allow a cell unrestrained, unlimited growth and are a cause of the massive growth of cells, known as a tumor. In this situation, cancerous cells have an advantage over normal cells, in that they have easier access to nutrient resources from the surrounding tissues and will grow until they are limited only by the availability of resources. An interesting observation is that the inner portion of many tumors is lower in oxygen (hypoxic), than the outer portions. This is a direct result of Fick's law of diffusion (http://en.wikipedia.org/wiki/Fick%27s_law_of_diffusion), which describes the flow of nutrients and oxygen from blood vessels into tissues. It shows that as a tumor grows increasingly larger, it becomes harder to provide cells further away from blood vessels nutrition. This is a natural limitation on cell growth and body structure, but tumor cells have a way to bend this rule, which is described in the next section.

2. Decreased dependence on natural growth factors:

Cancer cells are like 'rebels without a cause', the James Deans of human cells. Normally, the signals for growth are usually sent by the endocrine/paracrine system (http://en.wikipedia.org/wiki/Endocrine_system). Platelet derived growth factor, epidermal growth factor and insulin-like growth factor are just a few regulatory chemicals that trigger cell division and cell proliferation. The collective mass of these signals make up a system that tells cells when and under what circumstances to begin division. To have a body and the organizational benefits that it brings, individual cells must perform the tasks they've been assigned in the developmental process. Cancer cells, however, produce their own growth factors, often self signal and/or develop a means to receive more signaling. Since they require no outside signals for growth, they are not limited by this systematic control. They effectively work outside the system to effect their own self centered proliferation, at the expense of the body supporting them.

One example of this is an activity called angiogenesis (http://en.wikipedia.org/wiki/Angiogenesis), the production of new capillaries and blood vessels from main branches. Normally, fetal tissue relies on the function of vascular endothelial growth factor (VEGF) (http://en.wikipedia.org/wiki/Vascular_endothelial_growth_factor) to produce new capillaries in its rapidly growing tissues. More capillaries means that a greater volume of nutrients and oxygen can diffuse to important tissues. In adults, however, this process is usually indicative of cancerous activity, with wound healing and the female reproductive cycle being the major exceptions. Tumors produce VEGF to get around the limitations posed by Fick's law of diffusion. Tumor growth is limited to the short distance nutrients and oxygen can diffuse through tissues. Without the production of new blood vessels the mass of tumor cells would slowly starve.

VEGF has been found in almost every kind of human tumor and is at peak concentration around newly formed blood vessels and the hypoxic, inner regions of the tumors. Research has shown that by blocking VEGF by binding it to monoclonal antibodies, one can suppress tumor growth in mice(4). Other efforts are currently targeting VEGF receptors that are specific to kinds of tumors. Inhibition of a VEGF receptor called FLK1 has been similarly shown to reduce growth of tumors of certain cancer cell lines such as fibrosarcoma cell line HT-1080(5 (http://www.jimmunol.org/content/182/9/5537.full)).

Another method cancer cells use to circumvent normal regulation involves the over expression of epidermal growth factor receptors (6 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC387763/)). Normally, epidermal growth factor signals limited cell proliferation and its receptor is usually expressed in epithelial cells. However, cancer cells over-express it allowing for greater than normal signaling and as a result, increased proliferation. This over-expression is usually indicative of a poor prognosis, a situation occurring in many advanced stage cancers. In certain types of breast cancer, which comprise a little more than 20% of the total number of cases, the EGF receptor uses a protein called 'HER' to pass on the growth signal inside the cell. The bio-engineering giant Genentech recently made headlines for passing its drug herceptin (http://en.wikipedia.org/wiki/Herceptin) through clinical trials. This is a monoclonal antibody that specifically targets HER proteins. Since cancer cells that over express EGF receptors have a greater preponderance of this protein, they will be targeted for destruction by the immune system specifically over ordinary cells.

Recent drug advances have allowed for the selective targeting of these receptors, effectively blocking this excessive, cancerous signaling. Specifically, several new tactics have been devised to target these receptors and block their activation. Recent successes with monoclonal antibodies, selective toxins and small molecules that block receptor signaling activity have made it into general therapy. Monoclonal antibodies are specifically targeted to these receptors to bind and block them from being activated. Toxins can take a variety of roles to block receptor activity, whether as allosteric inhibitors or by covalently binding to the receptor's active site. Essentially, the end result is the same with these two kinds of weapons. With small molecule drugs, the tactic is usually to inhibit signal transduction from the receptor. The drug erlotnib (http://en.wikipedia.org/wiki/Erlotinib) is an example of this, in which it blocks a critical signaling component so signals can't be sent from the receptor. Erlotnib is from a class of drugs called tyrosine kinase inhibitors, that have found great usefulness as selective inhibitors of these kind of over-expressed tumor receptors.

3. Loss of anchorage in tissues and cell adhesion:

Normally, cells will undergo apoptosis once they become separated from their host tissue. It's tricky to grow normal cells outside of their home tissues, because they communicate with neighboring cells and require paracrine interaction for normal function. However, cancerous cells don't require these regulatory signals and can be grown in solution or on agar medium. Normal cells are usually held in place by a matrix of proteins and structural elements, as well as being linked directly to neighboring cells by physical junctions. These structural components often give important regulatory information to a cell. The point where this breaks down is the beginning of what is called metastasis (http://en.wikipedia.org/wiki/Metastasis), the ability of a cancer cell to travel to other tissues, invade them and start a tumor there.

Tumor cells express a set of metal containing enzymes called matrix metalloproteinases (http://en.wikipedia.org/wiki/Matrix_metalloproteinase) (MMPs). These are responsible for the matrix degradation seen in metastatic cancers. They chop away at the extracellular matrix holding them in place, eventually freeing the cells to do damage elsewhere. The expression of these proteins is considered indicative of progression to metastasis, because ordinary adult cells do not express them. High levels of matrilysin (http://en.wikipedia.org/wiki/MMP7) (MMP-7), for example, is a known indicator of prostate cancer. Additionally, MMPs are known for attacking cell to cell adhesion proteins like E-cadherins (http://en.wikipedia.org/wiki/E-cadherin), β-catenin and α-catenin. MMP-3, also known as stromelysin (http://en.wikipedia.org/wiki/MMP3), is known for cutting apart E-cadherin cell junctions. The loss of their function is a known cause of tumorigenicity and cancer cell invasiveness.

Once a tumor cell escapes it has two routes it can metastasize through: blood or lymphatic. The tumors often have patterns of invasion that are indicative of their tissue origin. For example, tumors of the head and neck are often spread through regional lymph nodes (7). Tumor cells manufacture special tools they use to attach to new host tissues called invadopodia (http://en.wikipedia.org/wiki/Invadopodia). These are similar in a way to bacterial pilli in that they contain various proteases and adhesive proteins that aid in attachment to the new cells and help the cell cross barriers.

The invadopodia bind to membrane components such as laminin, fibronectin, type IV collagen, and proteoglycans. Normally, these interact with receptor regulatory proteins called integrins (http://en.wikipedia.org/wiki/Integrins) that send regulatory signals to the cell. Cancer cells often change the binding preferences of their integrin receptor subunits to match those of degraded extracellular matrix proteins. The new types are thought to match the pieces damaged by MMP degradation and are often associated with invasive, metastatic cells (8). Binding to these pieces functions as a discovery signal that the cell has found a place that is susceptible to invasion. The fact that cancer cell integrin expression has changed in a distinct way, might also reveal a way to specifically target these cancerous cells. This could lead to therapeutic advances targeting the most aggressive, late stage types of cancers.

4. Loss of sensitivity to apoptotic stimuli:

Apoptosis is a form of cell death that is essential for tissue remodeling during embryogenesis and maintaining the number of cells in adult life. It functions to cull damaged, nonviable and potentially dangerous cells by acting as a failsafe that kills a cell when it has acquired too many mutations or unusual activities. It functions through cellular signaling pathways to block cell mitochondrial function, which eventually leads to the degradation of critical cell components and then ultimately, death.

The apoptotic program can be divided into three phases: initiation phase, decision/effector phase and the degradation/execution phase. The initiation phase typically is a response phase to outside stimuli, like death receptor ligands, or to inside stimuli like DNA damage. The decision/effector phase works to clarify the signal and open the door for action. Changes that occur in mitochondrial membrane permeability signal the end: the release of an key respiratory protein called cytochrome C (http://en.wikipedia.org/wiki/Cytochrome_c) into the cytoplasm. The degradation/ execution phase sees the activation of proteases (http://en.wikipedia.org/wiki/Proteases) and nucleases (http://en.wikipedia.org/wiki/Nucleases), which degrade proteins and nucleic acids, respectively. The key target is the mitochondrion, as well as other important cell machinery. As this is the main power source for the cell, this is typically fatal for it.

Apoptosis acts through signal transduction pathways controlled by receptors of the Fas cluster (CD95), tumor necrosis factor receptor 1 (TNRF1) and death receptors 3, 4 and 5 (DR 3, 4, 5). Each of these kind of receptors contains a special amino acid sequence called the "death domain (http://en.wikipedia.org/wiki/Death_domain)" that functions as a specific binding site for special death signaling proteins. These proteins pass the baton on to other proteins in the chain, much like a relay. Eventually they activate the main downstream effectors, the actual 'doers' of the hard work, the caspases. Caspases (http://en.wikipedia.org/wiki/Caspases) are a family of cysteine proteases that are responsible for much of the cellular degradation mentioned earlier.

The point of no return in this deadly relay is the release of cytochrome C, which is controlled by a set of proteins in the mitochondrial membrane that regulate its release. The first of these was identified in a cancer called B-cell lymphoma and was aptly named the B-cell lymphoma-2 (Bcl-2) protein (http://en.wikipedia.org/wiki/Bcl-2). This particular protein is a negative regulator of apoptotic signals. This group of regulatory proteins contains both positive (Bax, Bak, Bik, Bid) and negative regulators (Bcl-2, Bcl-x) of these signals. Positive regulators encourage apoptosis, whereas negative regulators discourage it. The key factor determining cytochrome C release is the relative ratio of positive and negative signals.

Cancer cells evade apoptosis by overexpression of Bcl-2. The Bcl-2 gene is usually moved to a different, more active location in the chromosome (typically the IgH promoter, a highly active portion). With more of this protein floating around, the pro-apoptotic signals are drowned out and sensitivity to them is significantly reduced. Lastly, cancer cells suppress apoptotic receptors by mutations that affect binding and proper function of the pathway. Slight mutations to the receptors or relay proteins can drastically affect the ability of the apoptotic signal to reach the critical stage.

5. Genetic instability:

Genetic instability is considered a major causative problem in cancers and one that we have few effective weapons against. Our battle strategy is reactive and revolves around destroying the cells that display these characteristics when they become a noticeable problem, which is often the time with the least efficacy in treatment. A truly proactive strategy will require advances in technology and bioengineering that will enable us to manipulate our genetic code, to edit out or silence problematic parts and correct mutations when they occur. The promise of gene therapy holds the hopes of many to pick up and wear that mantle, but these experiments are a ways off from useable therapies. Today though, like any good general, we make do with the tools we have on hand.

Cancer cells are often distinguished from normal cells by the loss or gain of a specific chromosome, or even the accumulation of an entire extra set of chromosomes. Extra chromosomes can provide cancer cells with extra copies of growth promoting genes. They can utilize these extra copies to amplify ordinary levels of signaling, causing the increased growth response and proliferation seen in tumors. Mutation is common in human tumors where changes at the sequence level can affect growth controlling genes, DNA repair or decreased fidelity during replication. Furthermore, it has long been known that misreplicated DNA can provide a causative explanation for some inherited cancer prone syndromes.

Translocations of genetic material from different chromosomes can lead to the abnormal gene expression seen in cancer. Chromosomal rearrangements, for example, are known to cause cancers like chronic myelogenous leukemia (CML) (http://en.wikipedia.org/wiki/Chronic_myelogenous_leukemia) and Burkitt's lymphoma (http://en.wikipedia.org/wiki/Burkitt%27s_Lymphoma). CML is caused by an abnormal chromosome, called the Philadelphia chromosome (http://en.wikipedia.org/wiki/Philadelphia_chromosome) (named after two scientists from Philly). In CML, two unrelated genes from chromosomes 9 and 22 switch places and parts of the genes are spliced together. This causes a new protein called "BCR/abl (http://en.wikipedia.org/wiki/Bcr-abl_fusion_protein)" to be produced that remains constantly active, driving cell division by activating cell cycle control proteins continuously and inhibiting DNA repair responses.

Fortunately, since CML is caused by a single protein, it represents a good target for drug based therapeutics. New tyrosine kinase inhibitors, like imatinib (http://en.wikipedia.org/wiki/Imatinib), are used to block BCR/abl's activity and has become the standard treatment for the disease over previous less specific antimetabolite chemotherapies and bone marrow transplants. This drug represents a different level of complexity in the treatment of the disease. An intimate molecular understanding of the disease, lead to the search for drugs that could effectively inhibit the protein's activity. Drug designers searched protein libraries, through thousands of possible candidates to find the best ones, eventually coming up with imatinib.

Imatinib is representative of a new kind of drug design, where a drug is designed from known specifications of the biological machinery. Specific understanding of the processes involved will ideally improve drug activity and binding specificity and hopefully open the door to more effective therapies. Even though it can not cure this disease, it makes management of the disease possible and improves the lives of patients over that of previous chemotherapy based treatments.

6. The Loss of Cell Cycle Control: Until next time...

jubei33
10th February 11, 01:33 AM
Some sources:

(1)http://en.wikipedia.org/wiki/Cancer (In epidemiology section.)

(2) Gale encyclopedia of cancer, pg. 11 intro, Helen A. Pass, M.D., F.A.C.S.

(3) http://en.wikipedia.org/wiki/P53

(4) ask me later, lost it...

(5)B. Millauer, M. P. Longhi, K. H. Plate, L. K. Shawver, W. Risau, A. Ullrich, and L. M. Strawn, Cancer Res., 56, 1615-1620 (1996).

(6) 60. N. Ferrara, and W. J. Henzel, Biochem. Biophys. Res. Commun., 161,851-858 (1989).

(7) Burger's Medicinal chemistry and Drug Discovery 6th ed., vol. 5 Chemotherapeutic agents. Wiley 2003. Pg12

(8) Burger's Medicinal chemistry and Drug Discovery 6th ed., vol. 5 Chemotherpeutic agents. Wiley 2003. Pg13

NoBowie
10th February 11, 07:46 AM
What does "molcular" mean?

EvilSteve
10th February 11, 09:42 AM
It would certainly seem that cancer holds the path to immortality if only we could control it, n'est-ce pas?

Speaking of which, have you read The Immortal Life of Henrietta Lacks? As you probably know, her tumor was the basis for the HELA cell line.

jubei33
10th February 11, 04:46 PM
No, I haven't actually. Is it good?

Some people, life extension proponents, think that by extending our telomeres and replacing those lost portions is the path to it, but I disagree. I think its primarily there so we don't get a pile of disfiguring cancers. Because most of these systems are intertwined, I don't think its going to be like that even remotely. Simply upregulating telomerase would most likely open the door for a plague of cancer and genetic disease. Another point is that we know of animals that already do this for some reason, but have ordinary lifespans.

It's not to say that its not possible, but I think that it will require a greater understanding of the biological machinery and the ability to rewrite it when necessary. These are things we have just only scratched the surface of. The newest technique for transinfection of genes, for example, was only able to infect ~10% of cells and only expressed the gene for 2 weeks in the best of cases (most were out after 2 days). I think its just going to be much more complicated.

EvilSteve
10th February 11, 05:02 PM
It's on my to-read list as soon as I finish Stranger in a Strange Land. Will let you know though.

I do agree, however, that telomerase = infinity lives is troll biology though. From my limited understanding, the genes that control longevity have little to do with that. However, clinical immortality would have to find some way of getting cells to avoid senescence without disabling their other death programs.

As for getting the new genetic code into all of a patient's somatic cells, that's a whole different can of worms. Last I checked, the only way I'd seen to do that is to use a viral capsid as a cloning vector. What's the new way?

Pie of Hate
10th February 11, 05:06 PM
With cancer being a gene defect... Does that mean its safe to smoke now?

EvilSteve
10th February 11, 05:12 PM
Yes, just be sure you only smoke pot.

Pie of Hate
10th February 11, 05:20 PM
I'll stick to the e-ciggie then.

Ajamil
10th February 11, 05:51 PM
With cancer being a gene defect... Does that mean its safe to smoke now?I'm pretty sure smoking has been shown to directly affect your genetic material.
(http://www.medicalnewstoday.com/articles/194813.php)

jubei33
10th February 11, 10:19 PM
It's on my to-read list as soon as I finish Stranger in a Strange Land. Will let you know though.

I do agree, however, that telomerase = infinity lives is troll biology though. From my limited understanding, the genes that control longevity have little to do with that. However, clinical immortality would have to find some way of getting cells to avoid senescence without disabling their other death programs.

As for getting the new genetic code into all of a patient's somatic cells, that's a whole different can of worms. Last I checked, the only way I'd seen to do that is to use a viral capsid as a cloning vector. What's the new way?

viral capsids have an inherent problem in that they usually encounter immune defenses, so this method hit snags a bit ago, especially with actually human tests using adenovirus. These dudes wanted to cure cystic fibrosis by adding healthy genes encased inside adenovirus shells, but ran into problems with incorporation into the genome, immune interferance and gene silencing.

newer methods utilize tailored plasmids with a payload of a complete, healthy gene and some transfection proteins to help its inclusion into the genome and for observation, like luciferase, etc...apparently there are DNA specific receptors that pick up DNA. Once inside the genes can hopefully be incorporated. These guys got up to 10% by direct injection into rat femoral arteries, with most of the transfected cells being located in organs with high blood throughput (#1 was liver, followed by heart lungs and kidneys).

Conde Koma
11th February 11, 04:30 AM
i love that you guys are smart.

so, is there any real difference between the kind of lumpy cancer that we think of when we think "cancer", and something like leukemia? or are they both caused by the same thing and will likely be cured by the same thing?

Dr. Socially Liberal Fiscally Conservative Vermin
11th February 11, 04:46 AM
newer methods utilize tailored plasmids with a payload of a complete, healthy gene and some transfection proteins to help its inclusion into the genome and for observation, like luciferase, etc...apparently there are DNA specific receptors that pick up DNA. Once inside the genes can hopefully be incorporated. These guys got up to 10% by direct injection into rat femoral arteries, with most of the transfected cells being located in organs with high blood throughput (#1 was liver, followed by heart lungs and kidneys).

WOW!!

jubei33
11th February 11, 07:50 PM
i love that you guys are smart.

so, is there any real difference between the kind of lumpy cancer that we think of when we think "cancer", and something like leukemia? or are they both caused by the same thing and will likely be cured by the same thing?
Most cancers cause tumors and they vary in complexity, the above 5 things are main causes of cancer. The sixth thing is probably the biggest and most important cause for cancer, the loss of cellcycle control. I left it out because of the format and it probably should be its own thread anyway( well to be fair, every one of those could be its own paper/book, but I did a lot of summarizing).

Cure depends on what you mean by 'cure'. If you mean ability to lead a normal life while its in remission, then a lot of cancers today are like that. For instance, 60 years ago testicular cancer was incurable, as in: 'if you got it you have 3 months to live' kind of incurable. But now, look at Lance Armstrong. Then there are some that, well, you aren't going to be so lucky.


WOW!!
Yeah, you said it. I've emailed these guys some questions and waiting for a response.