• Explain and discuss the meaning of the term "cancer"
• Describe the basics of Oncology
• Identify and describe the role of clinical trials in cancer treatment
• List and discuss the most common types of cancer
• Describe the basics of radiation therapy
• Explain what is meant by “chemotherapy” and discuss its key elements

The topic "Cancer" is profound and multifaceted. In reality, despite considerable advances in research and technology, it remains somewhat of an unsolved mystery to medical science. Even today, the media is full of confirmation of the “mystery” status of cancer. For example, the following article was published in the New York Times in August of 2006:

Scientists Begin to Grasp the Stealthy Spread of Cancer
August 15, 2006-New York Times-By Laurie Tarkan

The moment when a cancer begins to spread throughout the body - metastasis - has always been the most dreaded turning point of the disease.

Without metastasis, cancer would barely be a blip on the collective consciousness. Fewer than 10 percent of cancer deaths are caused by the primary tumor; the rest stem from metastasis to vital sites like the lungs, the liver, the bones and the brain.

Though chemotherapy and other treatments have lengthened the lives of people with metastasized cancer, no drugs have been specifically formulated to halt the process. That is because metastasis has remained something of a mystery until the last five years or so.

"In the last 30 years, we've learned all about identifying genes whose mutations initiate tumors," said Dr. Joan Massagué, chairman of the Cancer Biology and Genetics Program at Memorial Sloan-Kettering Cancer Center in New York. But these advances, he added, did not explain the metastatic process.

Now, knowledge of metastasis is beginning to accumulate to the point that new therapies are entering the pipeline. "In terms of milestones or breakthroughs, most of them are about to be made," said Dr. Massagué.

Dr. Patricia S. Steeg, chief of the women's cancers section of the Laboratory of Molecular Pharmacology at the National Cancer Institute, said she was optimistic for the first time. "The trickle is close, the first agents are in early clinical testing or will be soon," she said. "I'm very enthusiastic, much more than I was five years ago."

The complexity of metastasis may well have discouraged research. To metastasize, cancer cells have to acquire several dozen genetic alterations - in contrast with the handful typically necessary to initiate a primary tumor, Dr. Massagué said. Further complicating matters, each case of metastasis - breast cancer that spreads to a lung, for instance, or prostate cancer that spreads to bone - is genetically and molecularly different from the rest.

Studying metastasis is expensive and time-consuming, and it requires animal studies to track cancer cells that spread.

Dr. Danny Welch, professor of pathology at the University of Alabama at Birmingham, said scientists had avoided this area of inquiry. "There are under 100 people in the world whose labs focus on understanding more about how metastasis works," he said.

Scientists have long had a rudimentary understanding of the process. Some have estimated that a million cancer cells a day break away from a tumor roughly two-fifths of an inch in diameter and that maybe one in hundreds of millions will thrive. If it weren't so seldom, cancer would be far more deadly. More than 80 percent of cancers arise in the inside lining of organs. To metastasize, a cancer cell must break cellular bonds to dislodge itself, break down the mortar of the connective tissue, change shape and sprout "legs" that can pull it through the densely packed tissue.

After accomplishing this Houdini-like escape, the metastatic cell passes through a capillary into the blood stream, where it is tossed and tumbled and can be ripped apart by the sheer force of circulation, or attacked by white blood cells. If the malignant cell survives, it clings to a tiny capillary at another site, until it can eventually make its way out of that capillary into the tissue of a new organ.

In foreign tissue, the cancer cell, now called a micrometastasis, faces a hostile environment. The liver, for instance, is foreign territory to a breast cell. Some die immediately, others divide a few times, then die. Others stay dormant. The surviving cancer cells regenerate and colonize, becoming a macrometastasis that can be seen on diagnostic tests. As the metastasis grows, it becomes lethal by crowding out normal cells and compromising the function of the organ.

In recent years, scientists have begun to investigate each of these steps to identify the genes and their molecular products that drive the changes. Several emerging fields of study have generated excitement among cancer researchers. One focuses on the notion that the environment of the invaded organ, the microenvironment, plays a critical role in the metastatic process.

This is not an entirely novel idea. In 1889, the British pathologist Stephen Paget proposed the "seed and soil hypothesis," which suggested that the cancer cell depended on the secondary organ to thrive.

Today, it is well understood that an organ has to become somewhat receptive to the tumor. The more welcoming it is and the fewer hurdles it puts up, the easier it is for a cancer to survive. This theory partly explains why certain primary cancers prefer to spread to certain other organs. For example, breast cancers metastasize to the brain, liver, bones and lungs; prostate cancers prefer the bones, and colon carcinomas often metastasize to the liver.

"We've been focused on the seed for a long time, and we're now starting to understand more about the soil and the interaction between the seed and the soil," said Dr. Lynn M. Matrisian, chairman of cancer biology studies at Vanderbilt University. "In my mind, the real opportunity comes from understanding what makes a certain organ receptive to a metastatic cell growing there versus not receptive," Dr. Matrisian said.

Researchers are looking at a number of events that occur in the microenvironment that give a cancer cell a leg up as soon as it arrives. These changes involve both normal cells that reside in that tissue and the body’s roaming immune cells. "The tumor cells co-opt these cells to act in a way that's conducive for the growth of the metastasis," Dr. Massagué said.

There is evidence, for example, that a type of white blood cell, the macrophage, may help initiate colonization. It was once thought that high numbers of macrophages found in metastatic cancer colonies were there to do battle with the cancer. Now it is believed that they somehow promote factors that help tumors progress. Other normal cells are believed to make enzymes that loosen the cellular structure of the new host organ, making room for tumor cells to proliferate.

Another example comes from the understanding of bone metastasis. Breast cancer cells are known to activate normal cells called osteoclasts that break down bone. Bone is a dynamic tissue constantly being broken down and rebuilt. But when bone is degraded, it releases growth factors that incidentally fuel cancer.

Many people with bone metastasis are now being treated with a class of osteoporosis drugs known as bisphosphonates that inhibit osteoclasts. The idea is to prevent the breakdown of bone, and to interrupt the vicious cycle.

Taking the microenvironment theory a step further, some researchers are looking into differences in genetic makeup that can make one person more - or less - tumor-friendly than another. This could lead to a simple blood test to predict who is at risk for metastasis. The goal would be more customized treatment, and those at high risk would be treated more aggressively. Those unlikely to progress would avoid unnecessary and toxic treatments.

Dr. Kent Hunter, an investigator at the Laboratory of Population Genetics at the National Cancer Institute, recently performed a breakthrough study in mice, which provided evidence that the DNA of an organism plays an important role in determining the risk of cancer spreading. Dr. Hunter bred a strain of mice susceptible to metastasis with about 30 other strains of mice, and found that the offspring had varying rates of metastasis.

"Since these animals are all getting the same oncogene by breeding, the most likely explanation is that the changes are due to the differences in the genotype or genetic background of the mouse," Dr. Hunter said.

In an epidemiological study of 300 women with breast cancer from Orange County, Calif., Dr. Hunter identified two genes that were associated with an increased risk of metastasis, though a large number of genes are probably involved in a person's risk.

Another camp of researchers is looking at cancer cells for genes that can set off a whole set of steps, the so-called master regulators. A major question is how cancer cells seem clever enough to succeed in the many steps necessary to metastasize. Dr. Robert Weinberg, a professor of biology at the Massachusetts Institute of Technology, is a leading proponent of a contested theory suggesting that a tumor cell turns on an embryonic program that allows a cancer cell to relocate. "Over the last five years, it has become apparent that cancer cells don’t cobble together all these different talents, but they resurrect a previously latent behavioral program," Dr. Weinberg said.

He argues that a program, called the epithelial-mesenchymal transition, or E.M.T, is turned on in embryonic cells, allowing them to move to different parts of the body where they set up camp and build different types of tissue. According to Dr. Weinberg, these programs are turned off after embryonic development, but they are sometimes briefly turned on in wound-healing to build new tissue.

"Cancer cells opportunistically resort to turning on these programs, and in so doing, acquire all the traits that permit them to disseminate through the body," Dr. Weinberg said. "What remains unclear is whether or not all malignant carcinoma cells must undergo an E.M.T. in order to invade and metastasize."

Dr. Welch of Alabama added, "The problem is experimentally proving there is a turning on of E.M.T. and then a turning off of E.M.T. when the cell lands at the distant site."

Others are looking at cancer stem cells. Adult stem cells have the ability to renew themselves and generate new cells, but they can also become cancerous. Some experts believe that cancer stem cells are at the core of every metastasis. This would help explain why millions of cells can reach distant organs, but only a select few - presumably those with stem cell capacities - can initiate a tumor and colonize.

To date, cancer stem cells have been isolated from a small number of tumor types, and more research is needed to elucidate whether stem cells initiate metastases and where and how they acquire their renewal capacities. Most experts are looking at smaller pieces of the puzzle, many of them involving colonization, the final stage of metastasis. Upon diagnosis of cancer, experts suspect that many people already have micrometastases throughout their body. "The horse is out of the barn," Dr. Welch said.

Because colonization is the least efficient step in the spread of cancer, it seems like the Achilles' heel. A vast majority of cells that land in a distant tissue never succeed in growing and forming a macroscopic metastasis, Dr. Weinberg emphasized.

A number of laboratories have identified more than a dozen metastatic suppressor genes, which prevent micrometastases from colonizing but do not affect primary tumors. In metastatic cells, these genes - including NM23, Kiss1, MKK4, and RhoGDI2 - are either defective or inactive.

In several studies of mice, researchers have repaired defective metastatic suppressor genes and found that the tumor cells spread but did not colonize. In epidemiological studies, some of these genes that have been identified have been shown to be predictive of patient survival and metastasis, Dr. Welch said. Labs are now beginning to test agents that can activate the gene or repair it.

Other researchers are focusing on trying to halt the development of blood vessels that feed the micrometastasis in the process of angiogenesis. One of the first things a micrometastatic cell must do to thrive is call in new blood vessels, said Dr. Matrisian of Vanderbilt.

Drugs that inhibit angiogenesis have not proved that successful when used alone, but they appear to have lengthened some lives when combined with chemotherapy, said Dr. Lee M. Ellis, professor of surgery and cancer biology at the M. D. Anderson Cancer Center in Houston.Underlying these advances has been the shift in the understanding of metastasis - as many different processes rather than one simple mechanism, and different in each type of cancer. Each metastasis needs to be addressed separately.

"There are commonalities, from tissue to tissue, but what we're finding, unfortunately, is that we need to develop therapies for each specific site," said Dr. Steeg, of the cancer institute's Center for Cancer Research. "We used to think we only needed one pipeline to metastasis," she said. "Pharmaceutical companies now realize that they have to look at subsets of cancer, rather than at all of breast cancer."

"One advance can save many lives, but it's only one bite," Dr. Massagué, the Sloan-Kettering researcher, added, "because the next tumor type forming metastasis in the next organ needs to be addressed."

Cancer is the second among fatal diseases, next to cardiovascular diseases, in the industrialized countries and third fatal disease in India. It is estimated that in the next quarter of a century the number of new cancer cases globally is going to double, half of them in the developing countries. World Health Organization (WHO) has launched a campaign against cancer, with a three-fold strategy: prevent all the preventable cancers, cure all that can be cured, and reduce pain and discomfort where cure is not possible. In this context it may be worthwhile to examine the basic cellular changes leading to cancer development and to discuss some of the areas where strategies for prevention can be implemented.

Cancer is a broad term used for identifying a large number of diseases. Perhaps the only common feature of these diseases is the ability of uncontrolled cell proliferation that cannot be checked by the normal cell kinetics regulators. A normal cell suddenly turns into a rogue cell and start dividing continuously without check, leading to the development of solid lumps (tumors) or an abnormal rise in the number of dispersed cells like the blood corpuscles.

Cancer can occur in any part of the body and in any organ or tissue. Even though most of the cancers are generally associated with old age, no age group is immune to his disease. Cancer originates in our own cells, but several factors, both intrinsic and external to the body, which influence our daily life, can add to the life time cancer risk. While cancer, as such, is not infectious, some infections can act as a stimulus to induce and promote cancer development. In addition, environmental pollutants like many chemicals, industrial effluents, some therapeutic drugs, and mutagenic agents, including ionizing radiation, can increase the incidence of cancer. About 50% of all cancers are attributed to life style, e.g.. diet, tobacco habits and alcohol consumption, and exposure to industrial toxins.

The Process of Carcinogenesis

Cancer development is understood to be a multistep process. The concept of multi-stage carcinogenesis was first proposed in 1948 and supported by later studies. Present day oncology recognizes three main phases: initiation, promotion and progression. Initiation: Neoplasia initiation is essentially irreversible changes in appropriate target somatic cells. In the simplest terms, initiation involves one or more stable cellular changes arising spontaneously or induced by exposure to a carcinogen. This is considered to be the first step in carcinogenesis, where the cellular genome undergoes mutations, creating the potential for neoplastic development, which predisposes the affected cell and its progeny to subsequent neoplastic transformation. The human DNA sequences responsible for transformation are called oncogenes. Many of the active oncogenes have been isolated by molecular cloning, e.g.. human bladder carcinoma, Burkitt's lymphoma, lung carcinoma, carcinoma of the breast and several others.

Although the activation of more than one oncogene appears to be necessary for neoplastic transformation, the data imply that initiation may be induced with one hit kinetics. For example, in the human bladder carcinoma, a single point mutation converting the Ha-ras proto-oncogene into a potent oncogene was the first identified mutation in a human oncogene. Such tumor gene mutations can have profound effects on cellular behavior and response, and can lead to dysregulation of genes involved in biochemical signaling pathways associated with control of cell proliferation and/or disruption of the natural processes of cellular communication, development and differentiation.

Normal cells may bear the seeds of their own destruction in the form of cancer genes. The activities of these genes may represent the final common pathway by which many carcinogens act. Cancer genes may not be unwanted guests but essential constituents of the cell’s genetic apparatus, betraying the cell only when their structure or control is distributed by carcinogens.

However, the full expression of such neoplasia initiating mutations invariably requires interaction with other later arising gene mutations and/or changes to the cellular environment, but the initiating mutation creates the stable potential for pre-neoplastic cellular development in cells with proliferative capacity . The transformed cell undergoes continuous division with fidelity to the transformed karyotype and, possibly, with further mutations, before a malignant lesion is manifested.

Mechanisms of Oncogene Activation

Each oncogene is closely associated with a normal DNA sequence present in the cellular genome, the proto-oncogene. At least five different mechanisms are considered for the conversion of proto-oncogenes to active oncogenes:
(1) Overexpression of proto-oncogene following acquisition of a novel transcriptional promoter. The oncogene then acquires activity because their transcripts are produced at much higher levels than those of the related normal proto-oncogene.
(2) Over-expression due to amplification of the proto-oncogene or oncogene.

The increased gene copies cause corresponding increases in transcript and gene product.
(3) Influences on the levels of transcription and, in turn, the amount of gene product.
(4)Juxtaposition of the oncogene and immunoglobulin domains, following chromosomal translocations, that appears to result in
deregulation of the gene.
(5) Alteration in the structure of the oncogene protein. This is the most well documented mechanism in the case of the oncogene proteins encoded by the ras genes. The fourth and fifth mechanisms seem to be inter-related.

A translocation can disturb the regulation of an oncogene by:

a) providing a new promoter region or some other control element that would activate the
oncogene; or
b) altering the coding sequence of a gene, changing its protein product from a benign to a malignant
form.

A close association between specific chromosomal translocations and certain human neoplasms has been demonstrated. Promotion: The transformed (initiated) cell can remain harmless, unless and until it is stimulated to undergo further proliferation, upsetting the cellular balance. The subsequent changes of an initiated cell leading to neoplastic transformation may involve more than one step and requires repeated and prolonged exposures to promoting stimuli.

Thus, in contrast to initiation which is induced at a rate of 0.1-1.0 per cell/Gy of radiation, the subsequent transforming event in the initiated cells occurs at a rate of only 10-6 to 10-7 per cell generation.

Neoplastic development is influenced by the intra- and extracellular environment. Expression of the initial mutation will depend not only on interaction with other oncogenic mutations but also on factors that may temporarily change the patterns of specific gene expression, e.g.. cytokines, lipid metabolites, and certain phorbol esters. This may result in an enhancement of cellular growth potential and/or an uncoupling of the intercellular communication processes that restrict cellular autonomy and thereby coordinate tissue maintenance and development.

Progression: is the process through which successive changes in the neoplasm give rise to increasingly malignant sub-populations. Molecular mechanisms of tumor progression are not fully understood, but mutations and chromosomal aberrations are thought to be involved. The process may be accelerated by repeated exposures to carcinogenic stimuli or by selection pressures favoring the autonomous clonal derivatives. The initiated cells proliferate causing a fast increase in the tumor size. As the tumor grows in size, the cells may undergo further mutations, leading to increasing heterogeneity of the cell population.

In the first phase of progression, sometimes referred to as neoplastic conversion, the pre-neoplastic cells are transformed to a state in which they are more committed to malignant development. This may involve further gene mutations accumulating within the expanding pre-neoplastic cell clone. The dynamic cellular heterogeneity, a feature of malignant development, may, in many instances, be a consequence of the early acquisition of gene-specific mutations that destabilize the genome. Examples are mutations of the p53 gene or DNA mismatch repair gene. Many tumor types develop transforming sequences in their DNA during their progression from the normal to the cancerous state.

An elevated mutation rate established relatively early in tumor development may, therefore, provide for the high-frequency generation of variant cells within a premalignant cell population. Such variant cells, having the capacity to evade the constraints that act to restrict proliferation of aberrant cells, will tend to be selected during tumorigenesis.

Tumor metastasis: As the tumor progression advances, the cells lose their adherence property, detach from the tumor mass and invade the neighboring tissues. The detached cells also enter the circulating blood and lymph and are transported to other organs/tissues away from the site of the primary growth and develop into secondary tumors at the new sites. These form the distant metastases, resulting in widely spread cancers.

Cancer metastasis consists of a number of steps; the main steps are common for all tumors. The progress of the neoplastic disease depends on metastatic changes that facilitate:
(a) invasion of local normal tissues,
(b) entry and transit of neoplastic cells in the blood and lymphatic systems, and
(c) the subsequent establishment of secondary tumor growth at distant sites. Many of the steps in tumor metastasis involve cell - cell and cell - matrix interactions, involving specific cell surface molecules. Malignant cells are thought to have reduced ability to adhere to each other, so that they detach from the primary tumor and invade the surrounding tissues.

The behavior of tumor is influenced by the cell adhesion molecules, one of the most important of which are cadherins. Animal studies have shown that a down-regulation of E-cadherin expression, resulting in lower levels, correlated with metastatic behavior in vivo, suggesting that cadherins function as invasion suppressor gene products.

It is the metastatic process and tumor spreading that are mainly responsible for the lethal effects of many common human tumors. In many cases gene mutations are believed to be the driving force for tumor metastasis, with the development of tumor vasculature playing an important role in the disease progression .

Tumor angiogenesis: Tumor growth depends on the supply of growth factors and efficient removal of toxic molecules, which comes through an adequate blood supply. In solid tumors, efficient oxygen diffusion from capillaries occurs to a radius of 150-200(m, beyond which the cells become anoxic and die. Therefore, increase in tumor mass to more than 1-2 mm will depend on adequate blood supply through development of blood capillaries (angiogenesis). P. Schubik was the first to coin the term 'tumor angiogenesis'. But it was Judah Folkman who hypothesized the importance of tumor angiongenesis in the development and metastasis of solid tumors. His theories are widely accepted today. Folkman and colleagues established that tumor growth beyond about 2mm size could proceed only if a vascular supply is established. A number of tissue factors have been identified, which stimulate endothelial cell proliferation. These include the tumor angiogenesis factor, the vascular endothelial growth factor, angioproteins - ang-1 and ang - 2, transforming growth factors (TGFs), interleukin - 1, and platelet-derived endothelial cell growth factor.

Although the blood vessels that supply the developing tumors are derived from the host vasculature, their architecture differs considerably from that in the normal tissue. Tumor vessels are often dilated, saccular and tortuous and may contain tumor cells within the endothelial lining of the vessel (Jain 1989). Therefore, the blood flow in the tumor may be sluggish compared to that in the adjacent normal tissues and the tumor microvasculature may show hyperpermeability to plasma proteins.

Cancer Genes

Somatic gene mutations are widely accepted as the basic event in the conversion of a normal cell into cancer cell. Many different genes are demonstrated to be involved in carcinogenesis. The gene mutation theory of oncogenesis maintains that carcinogens interact with DNA resulting in irreversible changes in the gene (point mutations), which predispose the cells to malignant transformation. The somatic genetic changes in cells that contribute to multistage tumor development potentially involve sequential mutation of different classes of genes, i.e. Proto-oncogenes, tumor suppressor genes, genes involved in cell cycle regulation, and genes that play roles in maintaining normal genomic stability. Biochemical interactions between tumor gene mutations may destabilize the genome, compromise control of cell signaling, proliferation, and differentiation, and interfere with the normal interaction of cells in tissues.

Two classes of regulatory genes are directly involved in carcinogenesis, the oncogenes and the antioncogenes.
Oncogenes: They are positive regulators of carcinogenesis. In non-transformed cells, they are inactive (proto-oncogenes). Gene mutations can activate proto-oncogenes, resulting in a gain of function. Several proto-oncgenes were first identified through viral transformation of cellular genome, e.g.. c-erbB, cmos, c-myc, c-myb, C-H-ras. A large number of mutations in specific oncogenes - e.g.. ras, myc, etc. - have been found to be closely associated with different types of cancers.

Anti-oncogenes or tumor suppressor genes: They are negative growth regulators. Many human tumors, e.g. retinoblastoma, Wilm’s tumor, colon carcinoma, result from recessive mutation, which cause cancer when present on both homologues. These genes function as anti-oncogenes or tumor suppressor genes. In normal cells they regulate cell proliferation by checking cell cycle progression. Mutation in these genes results in a loss of gene function (the protein product will not be produced), which promotes carcinogenesis. Such gene mutations have been detected in several solid tumors, e.g.. cancers of breast, lung, rectum, etc., but only few such mutations have been seen in leukemias.

The two most widely studied tumor suppressor genes are the Rb gene and p53 gene. The proteins encoded by these genes inhibit cell cycle progression by blocking transcription of gene products necessary for transition from G1 to S phase. Mutation in the Rb gene could lead to loss of normal inhibitory control of cell cycle progression and, thereby, increase cell proliferation. This effect, coupled with genetic changes that cause loss of apoptotic signals, would enhance malignant transformation.

p53 has a major role in maintaining the genomic stability and cellular equilibrium. In normal cells, this gene promotes apoptosis, regulates cell cycle through G1 - S checkpoint control and induces cell differentiation. p53 participates in a cell cycle checkpoint signal transduction pathway that causes either a G1 arrest or apoptotic cell death after DNA damage. Mutations in p53, resulting in loss of function, will cause suppression of apoptosis, promote cell division by releasing the G1-S block and prevent differentiation of the cells, leading to neoplasm development. Mutations in the p53 gene are the most common genetic change observed in a large number of human malignancies; at least 50% of all human cancers have been found to contain p53 abnormality. Mutations in this gene have been observed in a wide range of human cancers like cancers of the breast, lung, colon, skin, urinary bladder, ovary and lymphoid organs. More than 500 mutations of this gene have been documented in breast cancer.

Theories of Carcinogenesis

Gene mutation theory:

This theory maintains that somatic gene mutations form the basis of neoplastic transformation and their clonal expansion leading to carcinogenesis. It is the most widely accepted and is supported by a large volume of experimental data. However, it does not explain tumor heterogeneity and aneuploidy and also the long latent periods between exposure to carcinogens and the development of tumors.

Aneuploidy theory:

Another theory that is currently gaining momentum is the aneuploidy hypothesis. According to this hypothesis, a carcinogen initiates carcinogenesis by a preneoplastic aneuploidy, which destabilizes mitosis. This initiates an autocatalytic karyotype evolution that generates new chromosomal variants, including rare neoplastic aneuploidy. The aneuploidy hypothesis provides a plausible explanation for the long latent periods from carcinogen treatment to cancer development and the clonality.

Epigenetic theory:

It has been recognized that non-mutational stable changes occur in cellular genome, which can contribute to carcinogenesis (Feinberg 1993 Cross and Bird 1995). Such events are broadly termed epigenetic and are thought to involve DNA methylation, genome imprinting and changes in DNA - nucleoprotein structure. Increased levels of methylated cytosine (one of the pyrimidine bases in DNA) results in the elevation of spontaneous mutation rates in the affected genome.

While each theory has its own merits, it may not be possible to assign an exclusive role to a single process alone in carcinogenesis. In many cases, a combination of the two or all process may work in cooperation.

An initiating somatic gene mutation can destabilize the genome and lead to aneuploidy and chromosome heterogeneity, characteristic of solid tumors, while epigenetic events can contribute to the neoplastic cell transformation and also facilitate promotional changes.

Factors Influencing Cancer Development

A number of intrinsic (biological) and external factors are associated with the development of cancers. The intrinsic factors include the age and hormonal status of the individual, familial history and genetic predisposition. The extraneous factors include diet and life style, individuals habits like smoking and alcohol use, exposure to toxic chemicals and radiation, some infections, etc. Several external factors, including asbestos, many chemicals, dyes, food additives, vehicular emissions, act as promoters in carcinogenesis.

Biological factors:

Age and hormonal status: Cancer is considered to be an old age disease. Some types of cancers are almost entirely found in people above 50-55 years, e.g. prostate cancer. Similarly cervix cancer in women are more commonly detected at the peri - or post - menopausal ages. However, no age group is immune to this disease.

Hormonal factors play an important role in the development of gender-specific cancers, e.g. estrogen in cancers of ovary and uterus in female.

Family history: Some cancers are indicated to have a link with familial occurrence. For example, women whose close relatives like grandmother, mother, maternal aunt or sister has suffered from breast cancer, are found to run about 3 times higher risk of developing breast cancer than those who do not have such a family history. Similarly, cancers of the uterine cervix (females) and of prostate (males) are also thought to have a familial connection.

Genetic predisposition: Certain genetic conditions are known to predispose the individual to cancer. For example, individuals with genetic conditions like xeroderma pigmentosum, ataxia telangiectasia, Bloom’s syndrome, and Fanconi’s anemia are found to be highly susceptible to different types of cancer.

External factors: Diet, alcohol, and tobacco use: More than 50% of all cancers are related to the diet and individual habits like alcoholism, tobacco chewing and smoking. High fat diet and obesity are associated with breast cancer. A positive correlation has been reported between age-adjusted breast cancer mortality rates and the average per capita fat consumption in a given nation on a daily basis. Similarly, deep-fried and burnt food and preserved (high salt) food are associated with increase in gastric cancer incidence. Regular consumption of food low in fiber content and rich in animal fat increased the risk of cancers of stomach and esophagus. High intake of red meat and low fiber diet has been considered to be the cause of the high incidence of gastric cancer in the USA. The role of cigarette smoking in lung cancer is established. Tobacco smoke contains a chemical, nitrosamine, which can induce neoplastic changes in the lung cells. Non-smoking tobacco habits, like chewing, are found to greatly increase the cancers of the upper alimentary tract and buccal mucosa. India has the highest incidence of oral cancers in the world, which is correlated with the tobacco chewing habit.

Alcoholism is found to increase the risk of liver and bladder cancers. Smoking combined with alcohol consumption poses a higher risk of cancers of the breast, esophagus, liver, stomach and urinary bladder. Alcoholism along with hepatitis B virus infection is a more serious risk factor in liver cancer.

Radiation and cancer:

Ionizing radiation is an established carcinogen, having both initiating and promoting effects. The positive correlation between ionizing radiation and carcinogenesis has been established from the studies on the early radiologists, radium dial painters and atom bomb victims of Japan. A positive association has been seen in the increase in childhood cancers and obstetric X-ray exposures of the mother. Tumors induced by radiation have relatively long latencies, which vary in different species as a more or less constant function. Within a given species the latency varies also with age at the time of irradiation and with the type of neoplasm induced. The age differences in latencies appear to be related to similar age differences in the rates of corresponding spontaneous leukemias. The risk of adult type of malignancies tend to increase progressively with time after irradiation, in parallel with the age-dependent increase in the underlying base-line incidence.

Viruses and cancer:

Oncoviruses play an important role in specific human cancers, e.g. human papilloma virus in cervix cancer, and certain skin cancer; Epstein-Barr virus in Burkitt lymphoma and nasopharyngeal carcinoma; hepatitis B virus in hepatocellular carcinoma; human T-cell leukemia virus in leukemia. The viruses are of two types: DNA viruses which incorporate into the cellular genome and the retroviruses (RNA viruses) which cause transformation of cellular genome, leading to malignant changes in the infected cell.

Role of free radicals:

Reactive oxygen species (ROS) and other free radicals are produced in the body, both during the normal metabolic process as well as by interaction with external toxic agents, for example, radiation and toxic chemicals. They include superoxide anions, hydroxyl radicals, peroxy radicals and hydroperoxides. These interact with DNA and produce gene mutations and chromosomal aberrations, leading to cell transformation. Free radicals are considered to have a major role in the induction of cancers by chemicals and radiation. Several factors of our modern life style, e.g. excess alcohol consumption, tobacco chewing and smoking habits, exposure to toxic chemicals and radiations, all add to the free radical production in the body and increase the risk of cancer.

Cellular Defense Mechanisms in Relation to Cancer Prevention and Carcinogenesis

Normal cells are naturally equipped with efficient defense mechanisms that work at different levels.

Antioxidants:

The cells synthesize their own defense molecules, which include the non-protein thiol gluthathione, and antioxidant enzymes like superoxide dismutase, catalase, glutathione peroxidase, reductase and S-transferases. These scavenge the ROS before they can reach the target molecules in the cell and thus protect against their attack on the vital molecules like DNA. Thus they serve as the biological watchdogs in safeguarding against free radical induced initiating changes, mutations and chromosomal aberrations. Many dietary ingredients like green vegetables, fruits, tea, spices and some diet supplements contain antioxidants. These include the vitamins A, C, and E, beta-carotene, alpha-tocopherol, ascorbic acid, flavonoids, lycopenes, curcumins and enzymes like caspasine. They act as chemo-preventers by scavenging free radicals and enhancing cellular defense through their adaptogenic properties.

DNA repair:

Damage to cellular DNA is the crucial early event in the neoplastic transformation of a cell. The DNA lesions may include altered bases, co-valent binding of bulky adducts, inter - and intra - strand crosslinks and generation of strand breaks. A range of alkylated products is formed in DNA by exposure to nitroso-compounds and other alkylating agents. Ionizing radiation and many genotoxic chemicals generate free radicals, which interact with DNA and produce different lesions ranging from base damage, deletions and complex and multiple lesions. Most normal cells possess a high capacity for repair of DNA damage. However, efficient repair depends on the type of damage, its severity and the time available for repair. The base damage and single strand breaks are repaired fast and without error, restoring the molecular structure. But double strand breaks and multiple breaks and local cluster lesions are not properly repaired and often contain errors (error-prone repair or misrepair), leading to cell death or cell survival with abnormal gene functions and chromosomal abnormalities which are associated with malignant cell transformation. DNA repair involves a number of genes, the products of which operate in a co-ordinated manner to form repair pathways that control restitution of DNA structure.

Apoptosis or programmed cell death is an important mechanism of cellular defense in reducing the risks of error-prone repair. Cells with DNA damage undergo apoptosis, thus preventing these cells from surviving and entering the proliferating cell pool and, thereby, preventing the possibility of tumor development. Apoptosis is a genetically controlled process involving p53, bcl2 and other genes. Mutations in p53 can block the tumor-suppressive effect by eliminating apoptosis, and, thus, allowing the damaged cells to survive and undergo proliferation. Some of the gene products that control cell cycle also influence apoptotic tendencies, e.g. c-myc, pRb, Tp53.

Role of Diet in Cancer Control

Researchers Doll and Peto (1981) were the first to point out an association between dietary constituents and cancer. A vegetarian diet is considered to be beneficial in reducing cancer incidence. Epidemiological studies have suggested that diets rich in vegetables, and fruits reduces the risk of certain cancers. For example, diets rich in fiber, vitamins A,C, and E, beta-carotene, retinols, alpha-tocopherol, polyphenols, and flavonoids, and minerals like selenium and zinc, have cancer chemopreventive effect. Fruits and vegetables are rich sources of chemopreventive chemicals. These include inhibitors of carcinogen formation, blocking agents (block conversion of procarcinogens to carcinogens), stimulators of detoxifying system, trapping agents (trap and eliminate potential carcinogens) and suppressing agents (suppress the different steps of the metabolic pathway leading to cancer).

A study in China showed a high incidence of esophageal and gastric cancers in a population whose diet is deficient in beta-carotene and vitamins C and E. An interventional program, where the diet was supplemented with beta-carotenes, vitamin E and selenium, produced a 20% reduction in the stomach cancer mortality over a period 5 years. WHO has recommended dietary intervention in the cancer control strategy for the new millennium.

Dietary intervention follows two approaches:

1. Intervention through supplementing with vitamins, antioxidants and other dietary factors.
2. Intervention through dietary modification in which target levels are established for consumption of meat, fat, fiber, fruits and vegetables

Conclusions

Cancer is a broad term to describe a large variety of diseases, the common feature of which is uncontrolled cell division. The process of carcinogenesis consists of three major steps: initiation, where an irreversible change is affected in the cellular genes; promotion, where the initiated cells expand by self-proliferation leading to abnormal growth and further mutations; and progression, where the cells detach from the primary tumor and invade other organs and tissues, forming metastatic growths. Angiogenesis plays an important role in the tumor metastasis.

Different types of cancer genes - oncogenes and antioncogenes (tumor suppressor genes) - are involved in cancer development. Gain of function mutations in the oncogenes, leading to abnormal cell proliferation, and loss of function mutations in the anti-oncogenes leading to suppression of cell differentiation and apoptosis, are the major events leading to cancer development. Chromosomal aneuploidy and epigenetic events are also thought to be important. Several factors like age, sex, genetic predisposition, along with extrinsic factors like diet, environmental pollutants, alcoholism and tobacco habits have a major role in determining the cancer risk. Dietary intervention as a cancer preventive measure is a primary agenda on the WHO program.

What is Cancer?

Cancer is the uncontrolled growth of malignant cells, which if left unchecked, can destroy organs or their functions. Oncology, the study of cancer and its treatment, is very complex, as more than 200 distinct forms of cancer have been identified and hundreds of chemotherapeutic agents are approved for the treatment of cancer. (By MaryAnn Foote, PhD Director, Global Regulatory Writing, Amgen Inc.)

The National Cancer Institute (NCI) has estimated that 1,334,100 people living in the US were diagnosed with some form of cancer in 2003 and that 556,500 deaths were attributed to cancer that year.1 The popular media are replete with reports of cancer prevention through diet, lifestyle modification, or early detection.

Cancer remains a frightening and mysterious disease that appears to strike indiscriminately. As biomedical communicators, we must understand the facts and avoid being swayed by sensationalism or rumors. Thus, it is important for biomedical communicators to understand the complex subject of oncology.

Definition of Cancer

The word "cancer" is derived from the Latin word for "crab." Because many tumors, or clusters of cancer cells, are capable of wildly uncontrolled cell division, malignant tumors often are thought to have the silhouette of a crab, with many appendages radiating from a central body. (Normally, cells form orderly layers or sheets of tissue.) Other names for a tumor are lesion, malignancy, mass, or neoplasm. Cancer cells are able to divide more rapidly than normal cells and can displace normal neighboring cells. Intrinsic changes in cancer cell composition allow them to multiply without the usual restraints placed on cells (i.e., most cells must "obey" territorial limits placed on them by their neighboring cells, but cancer cells do not); cancer cells appear to divide more rapidly than normal cells and fewer daughter cells undergo apoptosis.

When cells divide rapidly but keep within their normal territory and do not invade the surrounding tissues, the cell cluster is referred to as a benign tumor. Usually, benign tumors pose no threat, but if they are contained in an enclosed space, such as the cranial cavity, they can continue to increase in size and put pressure on an organ. For this reason, benign tumors are often removed.

Malignant cancers are capable of spreading through the body by 2 mechanisms: invasion and metastasis.

Invasion is the direct migration and penetration by cancer cells into neighboring tissues. Metastasis refers to the ability of cancer cells to penetrate into lymphatic and blood vessels, circulate through the bloodstream, and invade normal tissues elsewhere in the body.

Almost all cells in the body are susceptible to cancer, and more than 200 distinct varieties of cancers have been described. Most varieties of cancer are rare, and deaths due to cancer are mainly attributable to only a few common ones such as lung, breast, colon, skin, and blood cancers. Cancers are classified according to the type of tissue and type of cell in which they originate. For example, if the disease is believed to have originated in the tissues of the breast, the diagnosis may be breast cancer. The cancer may spread to other organs such as the lung, and the diagnosis would be primary breast cancer with lung metastases.

All cancers can be placed into 1 of 6 broad categories: carcinoma, sarcoma, leukemia, lymphoma, melanoma, and glioma. The different types of cancers are defined by the organ of the body in which the cancer started. Carcinomas originate in epithelial issues, such as the liver, lungs, glands (e.g., prostate or thyroid), bladder, kidney, breast, ovary, uterus, testes, colon, skin, and brain. Approximately 80% of all cancer cases are carcinomas. Sarcomas originate in bone, muscle, cartilage, fat, and fibrous tissue. Sarcomas are rare, representing approximately 1% of all cancers. Leukemias originate in the bone marrow; myeloma is a subset of leukemia and is a cancer of plasma cells. When cancers affect the blood or blood-forming organs, they are called myeloid; when the cancer involves other tissues that do not directly affect the formation of blood cells, it is referred to as nonmyeloid. Lymphomas originate in the lymphatic system, i.e., the lymph nodes.

Melanomas are cancers that originate in skin cells called melanocytes (although melanomas can be found in organs other than skin), and gliomas are cancers of the nervous tissue, i.e., the brain and spinal cord. Most organs of the body are composed of several types of tissue, which means that each organ can be the site of different types of cancers. For example, most cases of uterine cancer are carcinomas and are found in the endometrium of the uterus. Some uterine cancers, however, are found in the muscle of the uterus, classifying them as sarcomas.

Symptoms of Cancer

Symptoms of cancer can be silent, particularly in the early stages of development. Some symptoms are specific to certain types of cancer, such as difficult urination for prostate cancer or flu-like symptoms and easy bruising for acute leukemias. Sudden weight loss, a thickening or lump, unexplained bleeding, coughing, or a wound that will not heal are some of the many symptoms that may be related to cancer. Often, symptoms are nonspecific; that is, common to many other conditions.

Diagnosis of Cancer

Cancers are diagnosed a variety of ways, again depending on the primary source of the cancer. The biopsy, which involves surgically obtaining a small tissue sample and examining it under a microscope, is often used to help identify the primary cancer. A biopsy can be done on all tissues including the bone marrow. When examined microscopically, cancer tissue has a distinctive appearance, including a large number of dividing cells, variation in the size and shape of cells and nuclei, loss of specialized cell features and normal tissue organization, and poorly defined tumor boundary. Microscopic examination of a biopsy specimen will sometimes detect a condition called hyperplasia.

The cell structure and orderly arrangement of cells within the tissue remain normal, and the process of hyperplasia is potentially reversible. Microscopic examination of a biopsy specimen can detect another type of noncancerous condition called dysplasia, an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure. Often such cells revert to normal behavior, but occasionally they gradually become malignant. Because of their potential for becoming malignant, areas of dysplasia should be closely monitored and sometimes require treatment. The most severe cases of dysplasia are sometimes referred to as carcinoma in situ ("cancer in place"), which refers to an uncontrolled growth of cells that remains in the original location. Carcinoma in situ may develop into an invasive, metastatic malignancy and, therefore, is usually removed surgically, if possible.

Microscopic examination also provides information regarding the likely behavior of a tumor and its responsiveness to treatment. Cancers with highly abnormal cell appearance and large numbers of dividing cells tend to grow more quickly, spread to other organs more frequently, and be less responsive to therapy than cancers whose cells have a more normal appearance.

Based on these differences in microscopic appearance, oncologists assign a numerical grade to most cancers. In this grading system, a low number grade (grade I or II) refers to cancers with fewer cell abnormalities than those with higher numbers (grade III or IV). Disease progression is determined by the size of the tumor and its invasion into surrounding tissues, and metastases to regional lymph nodes or other regions of the body. Based on these criteria, the cancer is assigned a stage. A patient's chances for survival are better when cancer is detected at a lower stage number.

Another diagnostic tool is the endoscope, which can be used to examine major organs and the entire digestive system. Endoscopy is routinely used to screen for the presence of colon cancer. Radiographs (i.e., x-rays) ultrasonography, computed axial tomography (CAT; often called computed tomography or CT) scan, positron emission tomography (PET) scan, and magnetic resonance imaging (MRI) are other ways that tumors can be detected. Additionally, blood tests may help to diagnose cancers. Some tumors have tumor markers that include genetic markers, cellular and tissue markers, and circulating markers that can be detected in the blood.

A blood test for prostate cancer measures the amount of prostate-specific antigen (PSA), a tumor marker. Higher-than-normal concentrations of PSA may indicate cancer. Recently, a blood test for ovarian cancer, known as CA-125, has become available. It should be stressed that blood tests by themselves, however, are inconclusive because more than 300 markers have been identified but their relationships to cancer are not fully elucidated.

Presence of a tumor marker is not conclusive proof that a tumor exists.

• Change in bowel or bladder habits
• Sore that will not heal
• Unusual bleeding or discharge
• Thickening or lump in the breast or other part of the body
• Indigestion or difficulty in swallowing
• Obvious change in a wart or a mole
• Persistent cough or hoarseness

The biggest risk for the development of cancer is aging. The longer a person lives, the more likely it is that some form of cancer will develop. Some types of cancer are preventable (e.g., lung cancer from tobacco), while others types of cancer are caused by environmental factors (e.g., lung cancer in heavy smokers who use beta carotene supplements) or by genetic factors (e.g., MYC marker in lung cancer). Because cancer usually requires a number of genetic mutations, the chances of developing cancer increases as a person gets older because more time has been available for mutations to accumulate.

In addition to chemicals and radiation, bacteria and a few viruses can trigger the development of cancer. The bacterium Helicobacter pylori, which can cause stomach ulcers, has been associated with an increased risk for the development of gastric cancer. In the case of cancer viruses, some of the viral genetic information is inserted into the chromosomes of the infected cell, causing the cell to become malignant.

Very strong evidence suggests that the human papilloma viruses (HPV) are associated with most types of cervical cancer (squamous and adenocarcinomas), and results of several large studies suggest that HPV infection precedes the development of cervical cancer by 10 to 15 years. The use of tobacco products has been implicated in nearly 30% of cancer-related deaths, making it the largest single cause of death from cancer. Cigarette smoking is responsible for nearly all cases of lung cancer, and smoking has been implicated in cancer of the mouth, larynx, esophagus, stomach, pancreas, kidney, and bladder. Tobacco is the main environmental risk factor for lung cancer, and it has been estimated that each cigarette smoked shortens the smoker’s life by 14 minutes.

Skin cancer caused by exposure to sunlight is the most frequently observed type of human cancer. Because skin cancer is often easy to cure, the danger posed by sunlight is perhaps not taken seriously enough. Mortality may be low, but morbidity can be high if the lesions must be excised from a cosmetically sensitive area (i.e., the face). Chronic exposure to radiation in sunlight and fair skin that is susceptible to sunburns appear to be the most important risk factors, with increasing frequency of exposure, age, immune status, male gender, and DNA repair disorders (such as xeroderma pigmentosum) as other risk factors.

Drinking excessive amounts of alcohol is linked to an increased risk for several kinds of cancer, especially those of the mouth, throat, and esophagus. The combination of alcohol and tobacco appears to be especially dangerous: in heavy smokers or heavy drinkers, the risk of cancer of the esophagus is approximately 6 times greater than that for nonsmokers/nondrinkers. For people who both smoke and drink, the risk of cancer is 40 times greater than that for nonsmokers/nondrinkers. Alcohol cannot cause cancer but can convert damaged cells into malignant cells.

Studies suggest that differences in diet may play a role in determining cancer risk. In contrast to the clear-cut identification of tobacco, sunlight, and alcohol, the exact identity of the dietary components that influence cancer risk has been difficult to determine. Limiting fat consumption and calorie intake appears to be one possible strategy to decrease the risk of some cancers because people who consume large amounts of meat (rich in fat) and large numbers of calories have an increased risk for cancer, especially for colon cancer.

Causes of Cancer

Cancer is a multifaceted disease, sometimes the result of the unlucky convergence of genetics and environment. The etiology of cancer is different from the risk of cancer. Avoidance of the causes (etiology) of cancer may greatly reduce a person's risk of cancer. For example, smoking is a cause of cancer; not smoking reduces one's risk of cancer, even if he or she has a genetic defect that is a predisposition to cancer.

Genes and Cancer: Is Cancer Hereditary

All cancers are caused by a defect in a gene that allows the cell to proliferate wildly. The genetic effect occurs through small mutations in the DNA, little "hits" over many years. (Dr. Alfred Knudson developed the "2-hit" theory of cancer; he was the McGovern Award recipient at the 1999 AMWA meeting in Philadelphia.) Not all cancers are hereditary—actually only 5% of cancers are due to genetic inheritance. People born with the defective gene must still be subjected to prolonged or repeated exposure to a carcinogen.

Chemicals (e.g., from smoking), radiation, viruses, and heredity all contribute to the development of cancer by triggering changes in a cell's genes. The chemicals that trigger changes are called initiators. Chemicals and radiation act by damaging genes, viruses introduce their own genes into cells, and heredity passes on alterations in genes that make a person more susceptible to cancer. Genes are altered, or "mutated," in various ways as part of the mechanism by which cancer arises.

Several groups of genes have a role in carcinogenesis. The first group of genes implicated in the development of cancer are damaged genes, called oncogenes. Oncogenes are genes whose presence in certain forms and/or overactivity can stimulate the development of cancer. Cell growth and division is normally controlled by proteins called growth factors, which bind to receptors on the cell surface. This binding activates a series of enzymes inside the cell, which in turn activate special proteins called transcription factors inside the cell's nucleus. The activated transcription factors turn on genes required for cell growth and proliferation.

Oncogenes in normal cells can cause the cells to become malignant by instructing cells to make proteins that stimulate excessive cell growth and division. By producing abnormal versions or quantities of cellular growth-control proteins, oncogenes cause a cell's growth-signaling pathway to become hyperactive. A cancer cell may contain 1 or more oncogenes, which means that 1 or more components in this pathway will be abnormal. Oncogenes are related to proto-oncogenes, a family of normal genes that code primarily for proteins involved in a cell's normal growth. A second class of genes implicated in cancer are tumor suppressor genes.

Tumor suppressor genes are normal genes whose absence can lead to cancer. Tumor suppressor genes instruct cells to produce proteins that restrain cell growth and division. Because tumor suppressor genes code for proteins that slow down cell growth and division, the loss of such proteins allows a cell to grow and divide in an uncontrolled fashion. One particular tumor suppressor gene codes for a protein called p53 that can trigger apoptosis. In cells that have undergone DNA damage, the p53 protein halts cell growth and division. If the damage cannot be repaired, the p53 protein eventually initiates cell suicide, thereby preventing the genetically damaged cell from growing out of control. If a pair of tumor suppressor genes are either lost from a cell or inactivated by mutation, their functional absence can cause cancer.

Individuals who inherit an increased risk for the development of cancer often are born with one defective copy of a tumor suppressor gene. Because genes come in pairs (one inherited from each parent), an inherited defect in one copy will not cause cancer because the other normal copy is still functional. If the second copy undergoes mutation, cancer may then develop because there no longer is any functional copy of the gene.

A third class of genes implicated in cancer are called mismatch repair genes. Mismatch repair genes code for proteins whose normal function is to correct errors that arise when cells duplicate their DNA before cell division. Mutations in mismatch repair genes can lead to a failure in DNA repair, which in turn allows subsequent mutations in tumor suppressor genes and proto-oncogenes to accumulate.

People with a condition called xeroderma pigmentosum have an inherited defect in a mismatch repair gene. As a result, the DNA damage that normally occurs when skin cells are exposed to sunlight cannot be effectively repaired, and so the incidence of skin cancer is abnormally high for people with this condition. Certain forms of hereditary colon cancer also involve defects in DNA repair.

Cancer often arises because of the accumulation of mutations involving oncogenes, tumor suppressor genes, and mismatch repair genes. Colon cancer can begin with a defect in a tumor suppressor gene that allows excessive cell proliferation. The proliferating cells acquire subsequent mutations involving a mismatch repair gene, an oncogene, and several other tumor suppressor genes. The accumulated damage yields a highly malignant, metastatic tumor.

Another type of gene involved in the development of cancer is the telomerase gene. The end