CHAPTER 1 WHAT IS CANCER 

This book is designed to provide a detailed, but understandable, review of lung cancer. Specifically:

! By understanding the basics, you can direct your questioning to the details of your condition, rather than asking for general explanations about cancer and how it develops.

! Some decisions may not be made by the doctor alone. In many cases, there are experimental treatments. Knowing the medical basis for the treatment may help you make the decision of whether a particular clinical trial or other treatment is for you.

! Understanding what certain chemotherapy drugs are trying to do, and why certain side effects develop may help you to understand and deal with them.

1.01 Approach

As I worked on this book, a member of my family contracted cancer, and I realized firsthand the stress that diagnosis entails. Nonetheless I have tried to discuss lung cancer in a analytical fashion, laying out the facts and science even where they may paint a difficult picture, believing that being educated can only help the patient and his family. This is designed to be a middle book, more detailed than a general book about cancer, easier to read than a medical text. My goal is to lay out the science of lung cancer in a thorough, comprehensive, but understandable fashion.

1.02 Limits

Some caveats. This book is not designed to provide medical advice regarding any individual’s condition, and treatment alternatives may depend upon a number of individual factors. Cancer research is an evolving area, and some areas may have changed from the date of publication. There may be new studies and older ones may be reevaluated. Again, my goal is not to provide medical advice and you should make treatment determinations with the advice and guidance of your physician. My goal is to provide some basic information about lung cancer to make those consultations as meaningful and informative as possible.

1.1 COMMON CHARACTERISTICS OF CANCERS

1.11 Abnormal Growth

Cancer is a group of related diseases characterized by uncontrolled multiplication and disorganized growth of affected cells. Cancer is a significant disruption of the normal, orderly and regulated cycle of cell replication and division in the body. http://www.Intouchlive.com Cancers share three basic characteristics: unregulated growth, lack of cell differentiation, and the capacity to metastasize to neighboring tissues:

"{Cancer manifests itself as a population of cells that have lost their normal controls of growth and differentiation and are proliferating. In the first instance, these cells, derived initially from a normal cell, form a primary tumor (literally a swelling).... {This} primary tumor comprises a population of cells which are said to be growth transformed- that is they have acquired a set of mutations to a set of genes which allow them to divide repeatedly in a way that normal cells cannot." Vile, (1) at 24.

1.12 Cell Division and Multiplication as a Normal Process

Cell division and replacement is a normal process in the body. Cells in some parts of our body are constantly growing like fingernails and hair.

In other areas, cells divide to replace dead or damaged cells, such as in the skin or the intestinal tract. While one characteristic of cancer cells is their propensity to divide and multiply, normal cells do that too:

"Cells do all kind of things, including divide into more cells: one cell can divide into two cells, each "offspring cell" can divide into two cells, and so on. Cell division occurs at various times and for various reasons: cells divide during the growth and development of the embryo and the fetus, for example, and when there is a need to repair an injury in the body, such as a scraped knee. Cells also divide in cancer- cancer occurs when they divide out of control " Coleman (2)

1.13 Why Cell Division is Necessary

Cell division occurs for various reasons in the normal person. First, many parts of the body are subjected to daily wear and tear that kills or damages cells, and cell division is the body’s method of replacing these dead or damaged cells. Secondly cells may divide in order to perform certain tasks. When a germ enters our body, cells in the immune system divide and increase in number to kill the germ. Thirdly, cell division helps the body grow. Cell division is required for a child to increase in physical size and grow into adulthood.

Whether to replace old cells, perform specific functions, or help the body grow, cell division is usually a necessary and orderly process. Cell division is tightly regulated; with the cells signaled to divide only to perform specified functions. Normal tissue exists in a careful regulated balance of cellular division and cellular death. In contrast, cancerous tissue grows out of balance, resulting in an excess of cellular division.

Unregulated growth means a tumor grows without regard to the needs of the tissue or the normal controls for that cell or gene:

"In the first stage, a normal cell undergoes an initial genetic change which partly releases it from the normally very stringent controls imposed upon its growth potential; the daughter cells accumulate further genetic mutations which accentuate this loss of normal growth regulation, until a population of tumor cells emerge which no longer respond to normal signals preventing cell division and growth. The cells of the primary tumor are, therefore, said to be growth transformed. The genetic mutations which accumulate in these primary tumor cells are to members of two classes of cellular genes, the proto-oncogenes and the tumor suppressor genes. These genes control the ability of cells to pass through the cell cycle and, hence, their ability to divide or, alternatively to stop dividing and to undergo {differentiation]. " Dermer, (3)

Cancer is generally not unique behavior in a cell, but normal behavior expressed to an extreme or in an incorrect context. Division and duplication of cells, movement of cells to damaged areas, are each characteristics of normal cells. Even metastasis, movement of cells to other organs may occur with healing of wounds, the development of a fetus, or attacking bacteria.

1.14 Unregulated Growth

To call the growth of cancer cells wholly unregulated or unpredictable is inaccurate. Tumors possess certain common characteristics and we can to some extent predict how they will behave. Some types of tumors grow and divide rapidly, like small cell cancer, while others grow slowly.

1.15 Classifying Tumors Based Upon Growth Characteristics

Physicians classify tumors primarily upon their capacity to grow and move to other organs (metastasis). There are two main categories of lung cancer: small cell (sclc) and non-small cell (nsclc). Small cell tumors grow rapidly but are susceptible to chemotherapy while non-small cell tumors grow more slowly. I will later explain the categorization scheme for lung cancer.

1.16 Differentiation

Not only do cells divide to replace damaged or dead cells, they also develop to assume their final form and function in the body, a process called differentiation. Normal cells are differentiated, that is constructed or organized for a specific purpose. When a cell changes from a normal to cancerous one, the cell often loses some or all of its ability to form normally functioning tissue structures. Cancer cells are classified from well-differentiated to poorly differentiated, with the degree of differentiation one indicator of how the cell has changed. Under a microscope, a pathologist can look at the cell, determine and categorize its differentiation.

1.161 Well-differentiated and poorly differentiated cells

Well-differentiated means relatively limited changes are seen in the cell. A well-differentiated cancer cell may assume an appearance that is somewhat similar to its original tissue, and even display some normal functions. Poorly differentiated means the original structure and function is almost entirely absent. The extent of differentiation of the cancer cell is somewhat correlated with the aggressiveness of the tumor; poorly differentiated tumors tend to be far more aggressive than well-differentiated tumors. While the extent of differentiation is one factor in evaluating the status of the patient, it has not become a critical factor. Instead the extent of metastasis, or movement to other tissues, has become the chief factor in determining the status of the tumor and the treatment which will be administered.

1.17 Metastasis

Probably the most serious danger in cancer development is the tendency of cancerous cells to metastasize, that is, invade neighboring structures, and transmit the cellular malfunctions to those cells:

"Whereas a benign tumor will expand in size as a consequence of cell division, it will not invade surrounding tissues nor will it shed cells that are capable of initiating tumor foci elsewhere in the body. A malignant tumor will, however, actively invade and destroy surrounding tissue and also give rise to cells which often spread to produce foci of tumor growth at distant sites. Vile, (1) at 101-102.

1.171 Analogies to Normal Cellular Behavior

Metastasis, the movement of cancer cells to normal organs and structures seems strange. However the processes associated with metastasis are not unique to cancer cells and the ability of cells to travel to different areas of the body is a normal and necessary process to maintain health. For example, circulating white blood cells must be able to exit the blood through the capillaries and enter infected tissues in response to the injury. During early development of an embryo, cells that become the embryo’s placenta must be able to invade the mother’s womb to allow the developing embryo to attach and grow. Healing of a cut requires the movement of different types of cells to cover the wound and re-form skin and blood vessels. Each of these processes is tightly controlled such that the invasion is limited in time and space.

The body would likely repair the leg by replenishing cells and repairing damaged sources of blood supply. With a cancer, the body believes the area is damaged, so it connects with neighboring sources of blood and nourishment to replenish the damaged area. In truth, many cancers do reflect damage to DNA, but the remedy the body creates simply spreads the cancer, rather than repair the damage.

Comparisons to the behavior of normal cells can be made:

"It is also important to remember that expression of invasion promoter genes is not a purely pathological phenomenon seen only in cancer. Certain normal cell types demonstrate different elements of the phenotype as part of their usual functions. Thus, leukocytes resemble metastatic cells in many ways since they must leave the bone marrow and move, via the circulation to specific sites elsewhere in the body where they must penetrate to sites of infection and inflammation. Similarly, embryonic cells must move between developing tissues in a way that can be likened to tumor cell invasion.... Therefore, expression of the invasive phenotype by cancer cells should be thought of more as the activation of normal cellular programmes in an inappropriate cellular context, than as the expression of completely novel phenotypes. In this way, it may be possible to understand how and why the genes of invasion are expressed so aberrantly in tumor cells and, therefore, to generate more mechanism-based and effective treatments." (1) Vile, at 24

 

1.172 Tumors Are Categorized Based Upon the Extent of Metastasis

Cancers are categorized based upon the extent of metastasis (as well as growth). Non small cell lung cancers (the largest type of lung cancer) are classified from stage 1 to stage 4. Stage 1 tumors are limited to a defined area in a single part of the lung. Stage 4 means the tumor has metastasises to another organ, with stages 2 and 3 assessing the extent of movement to adjoining or distant lymph nodes. Stage one cancers are usually treated with surgical removal of the tumor, while stage four metastatic tumors treated with chemotherapy.

1.2 DIFFERENCES AMONG CANCERS

1.21 Cancer as a Group of Diseases

Cancers share the three traits of unregulated growth, loss of differentiation, and propensity to metastasize, though the extent of each trait may vary. Some cancers are highly metastatic meaning they move quickly to other parts of the body, while others move slowly over years or even decades. Most scientists believe that cancer is a group of related diseases with common characteristics, not a single disease. While cancers share certain characteristics there are significant differences among different cancers. Some skin cancers may be relatively harmless in their early stages, while others may be more serious especially in advanced stages.

1.22 Causes of Cancer.

The causes of cancers vary. Diet plays a critical role in the development of colon cancer, but has a limited role in lung, and perhaps no role in skin cancer. Nutrition plays a role in many cancers, but does not affect others. Given that the factors which create cancers vary, not surprisingly the resulting tumors themselves vary. Cancers behave differently depending upon their type and the organ where they originate.

1.23 Differences in Behavior of Different Cancers by Organ

The behavior of cancers depends primarily upon their type and the organ where they originate. Some cancers spread or metastasize very quickly while others are slow-moving. For example, pancreatic cancer is a very serious form of cancer, while some forms of skin cancer are relatively innocuous.

1.24 Treatment is Organ-specific

Treatment is generally by organ; a skin cancer is treated differently than a prostrate tumor. Clinical trials which test a particular drug may be limited to a tumors in a particular organ, or at least results will be categorized by organ.

Lung cancer is a solid tumor, unlike, for example, leukemia. There are some common traits among solid tumors and some of the same drugs are used for various types of solid tumors. Some drugs used for colon and breast cancer are used for lung.

1.25 Differences within the Same Organ

Since there can be different types of cancer in a particular organ, treatment within a particular organ can vary. As we see later, small cell lung cancer is treated differently than non-small cell.

1.26 Metastatic Cancer Cells Retain the Characteristics of the Original Organ

One writer explains:

"even though cancers enlarge, invade adjacent body parts, and travel to distant metastatic locations, they remain unchanged. The characteristics of human tumors, with rare exceptions, are fixed for the life of every tumor, regardless of where or when distant metastasises of the tumor are found. In 1874, Dr. W. Moxon, an English pathologist, described rectum in liver, referring to rectal tumors that were growing in their original unchanged forms after metastasizing to the liver.... a prostrate tumor that is diagnosed early prostrate specific antigen (PSA) was detected in the blood will continue to produce PSA years later at a metastatic site." Dermer, (3) at 46-47

 

Cancer is treated differently than non small cell lung cancer.

This book is about lung cancer, or more specifically tumors which originate in the lung. Thus, we may discuss metastasis to other organs, which will still be treated as lung cancer in most respects.

1.4 HOW NORMAL CELLS CHANGE TO CANCER CELLS

1.41 Proto-Oncogenes and Oncogenes

Cancer cells are basically good cells gone bad and we can, with some precision, identify those cells which can become cancers. These are genes already involved with cell division and growth which are called proto-oncogenes. "Mutations to a proto-oncogene alters its structure and activates it to produce an oncogene. The protein product of the oncogene is itself altered so that it can no longer be switched off by normal cellular signals and its expression directs the cell to divide" Vile, (1) 4-5

A proto-oncogene is a normal gene which performs certain growth functions but when altered, can turn into a cancerous oncogene:

"the beginnings of cancer lay not in a wholesale rewiring of the cell, but in a subtle alteration of a fistful of key genes among the human quote of DNA. Under normal circumstances, such genes play a vital, growth-related role in all or most tissues of the body. In some tissues, the genes may set up the rounds of simple division, helping skin cells to proliferate into a scab around a wound, or allowing the immune system to send out a host of antibodies to assail an invading pathogen.... Whatever their assigned tasks, the genes that scientists have designated oncogenes share a common characteristic: they are vulnerable to mutations. And once mutated, the genes contribute to the birth of a tumor...., it’s important to keep in mind that our cells possess oncogenes not because some nasty natural or supernatural force place them there to keep our population in check, but because the body requires the genes to grow." Angier, (4) at 5.

"An oncogene is a sequence of deoxyribonucleic acid (DNA) that has been altered or mutated from its original form, the proto-oncogene. Operating as a positive growth regulator, the proto-oncogene is involved in promoting the differentiation and proliferation of normal cells. A variety of proto-oncogenes are involved in different crucial steps of cell growth, and a change in the proto–oncogene’s sequence or in the amount of protein it produces can interfere with its normal role in cellular regulation. Uncontrolled cell growth, or neoplastic transformation, can ensue, ultimately resulting in the formation of a cancerous tumor." http://Www.brittanica.com Britannica (5) at 5. See excerpt in Cancer Medicine (15) for a more detailed summary.

It’s somewhat like an eight year old boy playing baseball in the house, a normal activity performed in the wrong context where it can do substantial harm.

1.42 How Oncogenes are Categorized

We have identified a number of proto-oncogenes and oncogenes. The term oncogene derives from the Greek term onco, meaning mass, and cancer is a mass of abnormal tissue. Genes and oncogenes can first be identified by a specific location such as chromosome 17. Oncogenes are also given specific names, which are usually three letter abbreviations such as myc, erb, or P53. Sometimes a prefix will be added such as v, for virus, indicating that the oncogene is associated with a virus, or c, indicating that the oncogene is associated with a chromosome defect.

1.43 Two Types of Oncogenes: Growth and

Tumor Suppressor Genes

At a basic level, two types of gene mutations combine to create a cancer. The first, is an abnormality of a gene involved with growth. An example is a gene that produces a protein that causes a growth-factor receptor on the cell's surface to be constantly on when in fact no growth factor is present. Thus the cell receives a constant message to divide.

The second type of gene which turns off the cell cycle and helps control cell growth is called a tumor suppressor gene. When the tumor suppressor gene malfunctions, the signal to the gene to stop duplicating is lost. Imagine a car. A car would travel when it wasn’t supposed to if the accelerator was on (growth-factor gene) or if the brakes were not functioning, (tumor-suppressor gene):

 

"To continue the analogy, ignition switches and accelerators (positive controls) start up the engines and get these processes moving, and brakes (negative controls) slow down or halt the processes when necessary. Like the cell cycle and apoptosis (cell death), the positive and negative controls comprise a series of modulations of protein activities through protein interactions and protein modifications." Griffiths (14)

Griffith’s description gives us more insight into the carcinogenic process. It is not one growth gene and one tumor suppressor gene which combine to create cancer. Instead there are multiple growth genes, multiple tumor suppressor genes, and a system of cellular communication which malfunctions, part of which we understand and a part we do not. Targeting the particular offending gene to develop a cure, particularly with lung cancer, has been difficult.

1.44 How Do Cells Know When to Divide:

Cells divide or perform other functions in response to signals or stimuli from other cells. "Cells sense signals from both the outside environment and other cells and, in response, they regulate protein expression and function:

"Although each cell carries an extraordinarily elaborate data bank in its genes, these genes cannot provide the cell with some very critical pieces of information. Genes cannot tell a cell where it is in the body, how it arrived there, or whether the body requires it to grow. Genes can only tell the cell how it should respond to external signals, which must come from elsewhere- from other cells, nearby and distant. Each cell in the body relies on a host of other cells to tell it where it is, how it got there, and what it should be doing." Weinberg, (5) at 97

What types of signals does a cell receive:

 

"Signals can be a direct reaction to a stimulus, such as the secretion of insulin by pancreatic B cells in response to increases in blood glucose. Signal release can be triggered by the nervous system in response to either external or internal cues, as in the release of epinephrine by the adrenal glands in response to stress. Signals can also be continuous, such as those sent by the extracellular matrix. Usually, signaling molecules are stored in the cells and are released to provide communications with other cells under specific conditions." (Devita 12).

Communication at the cellular level is called signal transduction. Cancer is really a signal transduction disease, in the sense that signals to replicate and perform other functions go awry, and cells are prompted to improperly replicate:

 

"The cell cycle is a highly ordered sequence of events that leads to cell growth and division. In normal cells, signaling pathways that detect signals from the cell exterior or interior tightly control the progression through the cell division cycle by regulating the activity of cell cycle control genes. In cancer cells, the deregulation of these signaling pathways or control genes can cause cells that are not dividing to enter the cell cycle and to begin to proliferate, leading to tumor formation." (Osip 16)

1.5 GROWTH FACTORS AND RECEPTORS

1.51 A More Sophisticated Model of Cancer Development

The simplest model of cancer is a proto-oncogene creating growth, and a tumor-suppressor gene failing to stop it. Were cancer creation that simple, scientists might be able to isolate either gene and develop a vaccine or treatment. Indeed, scientists have come close to identifying the source of particular forms of leukemia and certain childhood tumors.

Unfortunately with lung cancer, the model is more complex, with an interrelationship of many different cells signaling one another part of which we do not fully understand. "Our current state of knowledge of tumor suppressors show a picture of complex interactions between multiple suppressor genes with oncogenes to generate the malignant state." Devita (12)

As an analogy, consider juvenile crime. We know that lack of education, family instability, educational difficulties, and gang affiliation are all connected with crime. However, we do not fully understand the relationship between each component in terms of causation, which factor is most important, which causes which, and where intervention would be most successful. There are many parts to cancer, particularly lung cancer, which has made the task of inhibiting cell duplication difficult. (In comparison, with a few tumors, we have been able to isolate the cancer-causing gene). Even today with 40 years of research, the most effective treatment for lung cancer is simply removal of the tumor in its early stages, a treatment which has been known for at least the last 50 years.

1.52 Growth Factors and Receptors

Another model of replication is the growth factor and receptor. A growth factor connects with a receptor on a cell to start a process of cell reproduction, something like putting a screw in a nut. Newer forms of cancer gene therapy seek to interfere with this process. The epidermal growth factor connects with its receptor as part of the lung cancer process. The new drug Iressa is an epidermal growth factor receptor inhibitor. That is, it attempts to prevent the epidermal growth factor from coming in contact with its receptor. Interestingly, the drug seems to have success with some patients but not with others. Thus, there appear to be different characteristics of lung cancers and perhaps different pathways among patients with the same disease. "Several signaling pathways" appear to be affected by the epidermal growth factor. Welch (13)

1.6 HOW GENES ARE DAMAGED AND BECOME ONCOGENES

1.61 Types of DNA Damage

A normal gene can be damaged in a variety of ways. Part of the gene can be lost (deletion), or a gene could be rearranged and ends up in the incorrect location (translocation). A gene may initially be defective or an outside product can cause damage. For some diseases, we can identify the genes which are damaged:

In Burkitt lymphoma, a malignancy of immature B cells, one characteristic feature is a chromosomal translocation about 80% of the time, a translocation between the long arms of chromosomes 8 and 14 are involved; less frequently, a translocation between the long arms of chromosomes 8 and 2 or chromosomes 8 and 22. All three translocations found in Burkitt lymphoma involve a specific position on chromosome 8 (8q24) that is occupied by the cellular proto-oncogene/oncogene, c-myc. Cancergenetics (8).

1.62 How Throat Cancer Occurs

Let us look at a model explaining the development of throat cancer:

Repeated exposures of high concentrations of alcohol were know to kill many of the cells lining the mouth and throat. The surviving cells in the tissues lining these cavities would then received orders to grow and divide to replace their fallen comrades. These repeated rounds of growth and division would yield mutations in the DNA of these cells. Moreover, it seemed that DNA in the midst of replication was even more susceptible to damage from mutagens than DNA from nonproliferating cells. This explained why cigarette smoke, which contains dozens of different mutagens, and alcohol, which promotes cell proliferation, were a deadly combination. When used together, they generated as much as thirtyfold increase in risk of mouth and throat cancer. Weinberg, (6) at 59

1.63. Cancer generally involves Multiple incidents of DNA Damage

While one instance of damage to the cell will usually not impair its form or function, the cell can be destabilized such that it becomes more susceptible to future damage. This is termed "genetic instability".

For example, the inactivation of certain DNA repair genes, may allow the buildup of genetic mistakes with each succeeding round of cell division. Inactivation of a tumor suppressor, may allow propagation of an occasional DNA copying mistake to the next cell division. Each event builds on itself.

1.64 Apoptosis

The body has a inherent protection against the development of cancer- apoptosis, or programmed cell death. Certain cells detect abnormalities and trigger cell death. This carefully regulated system prevents many cells with abnormalities from developing or dividing.

1.65 Time for Cancer to Develop

Since cancer requires the abnormal development of a growth factor, probably multiple defects in tumor supressor genes, and the failure of the apoptosis system of cell death, we can surmise that cancer would take years if not decades to develop. Cancer increases with age, and most tumors are associated with a series of changes that occur over a period of 10 to 15 years or even longer.

1.66 Initiation Promotion Hypothesis

Many scientists see cancer development in different stages:

 

"The initiation stage is characterized by the conversion of a normal cell to an initiated cell in response to DNA damaging agents (genetic damage indicated by an X). The promotion stage is characterized by the transformation of an initiated cell into a population of preneoplastic cells, a result of alterations in gene expression and cell proliferation. The progression stage involves the transformation of the preneoplastic cells to a neoplastic cell population as a result of additional genetic alterations." Greenwald (13)

Greenwald suggests we stop seeing cancer as a defined event, for example the diagnosis of cancer. Instead, we would look to identify genetic damage and attempt to cure or correct it before it develops into a tumor. Some scientists call this chemoprevention using biomarkers to tell us which genes or cells have been damaged. "Acceptable biomarkers for cancer must be reliable (repeatable), highly sensitive and specific, quantitative, readily obtained by non-invasive methods, part of the causal pathway for disease, capable of being modulated by the chemopreventive agent, and have high predictive value for clinical disease." (Greenwald (13). With the concept of biomarkers, we could identify damage in a smoker before a tumor has developed. Accepting the concept of biomarkers has been much easier than reaching agreement on a specific biomarker. Researchers in clinical trials are now taking various measurements to determine what changes confirm or presage the development and spread of disease.

1.7 HOW CANCER SPREADS

There are two basic ways that cancer metastasize, that is spread to other organs. The most common route is by channels that exist in every part of the body called lymph channels. Lymph channels are a fine network of vessels that carry the liquid portion of the blood from different parts of the body. Returning to the bloodstream, the lymph is filtered through lymph nodes and returns to a large lymph vessel near the heart. Given the flow of lymph to and from the lymph nodes, we can understand why the finding of cancerous cells in the lymph nodes will be critical. If the tumor has moved to a lymph node, its potential for dissemination throughout the body increases. A tumor which is detected and removed before a lymph node becomes cancerous has a far better prognosis than one which has infiltrated a nearby lymph node.

1.71 Regional and Other Lymph Nodes.

In staging the patient, that is ascertaining his status, doctors consider whether the lymph nodes are cancerous, and where the cancerous nodes are located. The spread of a tumor to a lymph node located near the tumor, or a regional node, is less serious than the spread to one further away, indicates a greater spread of the tumor. A surgeon will generally obtain samples or biopsies from lymph nodes to ascertain whether the status of lymph nodes, and treatment will depend upon that assessment.

1.72 Blood Vessels

A tumor may also spread through the body through a blood vessel. There are various tests to ascertain the extent of cancer in the blood however, blood vessels cannot be individually assessed as lymph nodes usually are.

 

REFERENCES

Note on Organization

Following the format of many scientific journals, each reference is given a number.

1. Vile, Cancer Metastasis: From Mechanisms to Therapies(Wiley & Sons 1995).

2. Coleman, Understanding Cancer (Johns Hopkins Press 1998).

3. Dermer, The Immortal Cell 46-47 (Avery Pub. Co. 1994).

4. Angier, Natural Obsessions 5 (Mariner Books 1999)

5. www brittanica.com. (Cell Division and Growth)

6. Weinberg, One Renegade Cell (1998).

7. Lau, Clinical and Molecular Prognostic Factors and Models for Non-Small cell Lung Cancer, in Pass. Lung Cancer 604 (2001). http://www.cancergenetics.org

8. www.cancergenetics.org

9. www.Brittainica.com (Cytokines). Brittanica online provides detailed but understanding information for the general public on a number of specialized topics and is a good beginning for much research.

10. www.growth-factor.net

11.Greenwald, Science, medicine, and the future, Cancer chemoprevention, BMJ 2002;324:714-718

12. Devita, Cancer, Principles and Practice of Oncology (Lippincott, 2001).

13. Welch, Erb B Expression and Drug Resistance in Cancer, Signal, vol. 3, iss 3 (2002).

14. Griffith, Modern Genetic Analysis (1999).

15. "Proto-oncogenes are normal cellular genes that control cell growth (i.e., proliferation), specialization (i.e., differentiation) and death (i.e., apoptosis). Almost all proto-oncogenes encode a protein component of the signal transduction cascade. This integrated, multi-process system is responsible for the smooth, orderly, and specific transmission of extracellular signals to the nucleus, and this process regulates gene transcription with respect to replication. When proto-oncogenes are activated, they are termed oncogenes. Oncogenes exert a positive driving force for cell growth by their failure to desist in response to the absence of stimulation." Holland, Cancer Medicine, 2000) available on line at www.ncbi.nlm.nih.gov/books /entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10354710
16. www.osip.com

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