The proteins encoded by protooncogenes appear to be important for cellular growth and differentiation and are expressed in a highly regulated fashion at specific times and in selective tissues. There is an extremely long list of protooncogenes that are very diverse in nature and, when activated, participate in cellular transformation by driving excessive cell proliferation forward. As a consequence of this activation, one of the two copies (also known as alleles) of the genes inherited from both parents is altered or mutated with deleterious consequences for the cell. Protooncogenes exhibit a dominant phenotype at the cellular level in the sense that the altered copy represents a gain of function mutation. It then overrides the function of its normal allele and is sufficient to produce an oncogenic effect.
As the name indicates, tumor suppressor genes function to suppress neoplastic growth of cells. Mutations in these genes impair this growth-suppressor mechanism by removing the brakes from the cell, which results in uncontrolled growth. The inactivation of tumor suppressor genes in human tumors was first proposed by Alfred Knudson in 1971 when he described his landmark "two hit" model, where at least two "hits" or mutations targeting the same gene are required for the evolution of cancer.
According to this concept, predisposed individuals inherit one mutant copy of the gene from one of the parents, thus carrying the mutation in all cells of the body. Individual cells that give rise to tumors of specific tissues acquire the second mutational event, which usually occurs as a loss of the chromosomal region carrying the gene. Sporadic or nonheritable tumors develop in individuals who do not inherit mutations and therefore require two independent mutations in the same cell in both copies of the relevant gene (Figure 2). Thus, this theory unites both the heritable and sporadic forms of cancers.
There is persuasive evidence for the functional inactivation of tumor suppressor genes in many human neoplasms. This classical paradigm of tumor suppressor genes, first proven in retinobalstoma, has now been extended to many other human cancers and has become a central dogma in cancer genetics. More than two-dozen tumor suppressor genes have been cloned so far from a variety of human tumors.
In stark contrast to the dominant nature of mutations in protooncogenes, tumor suppressor genes are recessive in the heterozygous state, meaning their presence is masked by the normal allele. Also, as opposed to activating and gaining the function mutations of protooncogenes, mutations inactivate tumor suppressor genes and result in the loss of function.
During the replication phase of the cell cycle, three billion bases of the human genome are duplicated. To maintain the fidelity of this replication process, several genetically controlled and elaborate mechanisms have evolved that function as "spellcheckers" to repair the damage to DNA. In the case of DNA damage, which may be a consequence of endogenous random errors of the DNA replication machinery and/or exogenous insults caused by radiation, chemicals or ultraviolet light, specific mechanisms for repairing specific errors are activated. Conceivably, mutations in the genes encoding the components of this DNA repair machinery involved in proofreading and correcting random and/or specific types of errors that can eventually result in cancer.
A defining feature of cancer cells is to ignore growth inhibitory signals and continue dividing under conditions that do not permit the growth of normal cells. During normal cell division, a molecular network of enormously intricate and regulated events and feedback mechanisms, generally referred to as the cell cycle clock, controls the replicative process. The cell cycle clock is comprised of four major phases termed as G1 (first gap phase in which cell increases in size and prepares to duplicate its DNA), S (synthesis of DNA with precise duplication of chromosomes), G2 (second gap phase in which cell prepares for the final phase) and M (in which the parent cell divides to produce daughter cells) (Figure 3).
Cancer, in essence, appears to be a disease of the cell cycle. As a group, mutations in a variety of cell cycle genes probably constitute the most common genetic abnormality in cancers. Understandably, both protooncogenes and tumor suppressor genes are centrally involved in the control of cell division. The unconstrained proliferation can largely be explained by the gain of positive regulators or the loss of negative regulators of the cell cycle machinery and is an obvious target of antiproliferation strategies. Blocking the progression of a cell cycle will be most effective by an appropriate strategic design targeting the right activators or inhibitors of that cell cycle. Besides using cell proliferation as a target to limit tumor growth, anticancer strategies can be directed to induce cell suicide or to limit the life span of cells.
One of the popular therapeutic strategies targets the vasculature of tumors that provides oxygen and nutrients to the proliferating tumor cells. In solid tumors, formation of new blood vessels occurs by a process of sprouting from preexisting vessels and is known as angiogenesis. During the process of angiogenesis, endothelial cells (which are the principle cell type of blood vessels) proliferate and migrate to form new vasculature. Thus, a tumor's vasculature is composed of normal endothelial cells, which, in contrast to tumor cells, would be less prone to become drug resistant when targeted by antiangiogenic therapies.
The rapidly emerging molecular information provides critical insights as well as new opportunities to develop molecular and targeted approaches to cancer prevention, detection and treatment. Although entirely different cancers often share a variety of mutations, some mutational events are unique to specific tumor types. Thus, the molecular blueprints of cancer cells are not only distinct from their normal counterparts, but are also expected to be different from each other. Based upon the information obtained from these unique molecular signatures, specific therapeutic strategies can be designed for each tumor type.
The remarkable progress in the molecular dissection of carcinogenesis is only paralleled by the development of highly sophisticated technologies to analyze and diagnose the molecular alterations with unprecedented sensitivity and specificity. The recent advances, both in the molecular insights into various cancers and emergence of sophisticated high-throughput technologies, enable us to embark on new and formidable initiatives. An example of this is fingerprinting pure populations of cancer cells through various stages of their development. This device is a recent technology that has revolutionized our ability to diagnose, analyze and monitor cancer cells is the gene-chip technology that has the capability of scanning large genes for mutations in a very short period of time. It also has the phenomenal capability of monitoring the expression of thousands of genes in parallel.
It is also possible now to analyze differential expression between matching normal and cancer cells for genes from multiple signal transduction pathways, enabling us to monitor the expression of not single genes or a limited number of genes, but various signaling networks and pathways. Furthermore, expression chips are being used as a high-throughput screening procedure, making it possible to analyze literally thousands of tumors simultaneously.
Expression chip technology is being used for the molecular profiling of neoplastic lesions and will provide fundamental insights into the molecular alterations that subvert the normal cellular processes. It will uncover specific molecular markers for cancer detection/prevention and will identify molecular differences among tumors, which otherwise appear to be similar or even identical by conventional analyses. It will allow us to determine, at various stages of cancer development, which molecular targets will be useful for a specific cancer and therefore which therapies will be appropriate. Thus, it will provide a basis for identifying markers for early detection and also greatly enhance the drug development process.
Despite the remarkable progress in understanding the mysteries of cancer, untangling the genetic events leading to cancer represents an endeavor that is far from over. However, based on the rapidly emerging molecular information of cell biology and innovative sophisticated technologies, a cautious optimism that someday cancer therapies will be customized to take into account both the molecular diagnosis of cancer and the genetic makeup of the patient seems warranted
Cancer is a cumulative name for more than 100 distinct diseases. It is a highly complex genetic disorder characterized by multiple genetic abnormalities that usually accumulate over a long period of time. The quest for an understanding of the basic mechanisms involved in human cancers has provided important insights into the workings of normal cells with highly regulated growth and how these regulatory pathways go awry in cancer cells. 
