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The nature and development of cancer 

The nature and development of cancer

Chapter:
The nature and development of cancer
Author(s):

John R. Benson

and Siong-Seng Liau

DOI:
10.1093/med/9780199204854.003.0602
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date: 27 April 2017

Contemporary ideas of carcinogenesis envisage a series of random genetic changes that confer a selective growth advantage over healthy cells. These changes collectively lead to the disruption of coordinated networks of intercellular communication and cause a fundamental change in cellular behaviour which affects processes such as proliferation, differentiation, and apoptosis. This progressive dysregulation of cellular function implies that cancer is not a morphological entity, but a process in which the malignant phenotype is gradually acquired.

Why are cells prone to become cancerous?

Cells have an inherent programme which influences rates of proliferation, differentiation, and cell death, but the rate of these processes is determined by the balance of positive and negative growth factors to which they are exposed. Whatever the mechanistic fault, aberrant function of these growth factor loops leads to excessive proliferation, promotes immortalization of cells, and in turn leads to neoplastic development.

Why do cells respond to multiple mitogenic growth factors? From a teleological perspective, these may guarantee a rapid growth phase during the early stages of embryogenesis, thereby maximizing the chances of sustained viability, and functional redundancy in the system may be an evolutionary safeguard to ensure an organism’s survival in adverse circumstances where specific growth factor pathways are compromised and would otherwise threaten survival.

The process of carcinogenesis

Oncogenes and tumour suppressor genes—the malignant phenotype is thought to arise from an accumulation either randomly, or sequentially, of alterations within two operational classes of gene. (1) Oncogenes—these are derived from normal cellular counterparts termed proto-oncogenes, which code for a variety of proteins including polypeptide growth factors and their receptors, some key components of the signal transduction process, and nuclear regulators of the cell cycle. Activated oncogenes represent a positive or ‘gain-of-function’ change resulting in a growth advantage over normal cells. (2) Tumour suppressor genes—these are genes which exert a negative (suppressive) influence on cellular proliferation and promote pathways leading to programmed cell death. Mutations leading to loss of function remove a kind of ‘brake’ on the cell cycle or impair mechanisms involved in the maintenance of genomic integrity and fidelity of DNA replication.

The Knudson ‘two-hit’ hypothesis—this states that mutations in both alleles of a gene pair are a prerequisite for cancer development. Individuals with an inherited predisposition to cancer already possess a mutation in one allele (present in all cells) and thus require only one further somatic mutation for tumour formation, whereas sporadic forms of cancer are dependent upon two somatic mutations. This hypothesis is especially applicable to those tumours arising from loss of function in tumour suppressor genes, because inactivation of both alleles is usually essential before levels of the gene product fall sufficiently to induce malignant change; it is of less relevance to cancers produced by oncogenes.

The basis for malignant transformation—genetic alterations within a cell can be either inherited or acquired. Most human cancers are sporadic (meaning that there is no inherited risk) and these are dependent exclusively on somatic mutations, which result from one of two inter-related processes: (1) the intrinsic error rate for DNA synthesis and repair; and (2) augmentation of the spontaneous mutation rate by environmental factors interacting with cellular DNA either directly or indirectly, e.g. radiation and chemical carcinogens. These processes may (1) initiate tumour development—by producing a permanent change in cells, but insufficient to cause tumour development without other factors; and/or (2) promote tumour development—by inducing division of a cell that has been ‘initiated’.

The origin of cancer cells—most human cancers are monoclonal, implying that a single cell undergoes malignant transformation and forms a primary clone from which further subclones are derived. It was previously believed that cancers arose from dedifferentiation of cells of mature phenotype, with reversion to a more primitive state to a greater (poorly differentiated) or lesser (well differentiated) degree. However, it is unlikely that mature somatic cells exist within tissues for a sufficiently long period to accumulate a mandatory number of mutations for malignant transformation. By contrast, stem cells have greater longevity and the capacity for self-renewal. The cancer stem cell hypothesis proposes that the stem cell is the target for carcinogenesis and not mature somatic cells.

The malignant phenotype

Cancer cells possess the following in vitro characteristics: (1) reduced requirement for exogenous sources of polypeptide growth factors; (2) loss of contact inhibition once confluency is reached; (3) anchorage-independent growth; and (4) the ability to divide indefinitely after multiple passages in tissue culture (immortalization). Cells that have acquired these properties are referred to as ‘transformed’.

Characteristics of malignant neoplasms—loss of responsiveness to normal growth control mechanisms is a hallmark of any tumour, but malignant neoplasms have three characteristic features: (1) growth is no longer subject to strict regulation by surrounding cells and tissues; (2) anaplasia or loss of cellular differentiation; and (3) the propensity to metastasize and form tumour foci at distant sites.

Clinical implications

Increasing understanding of the pathobiology of cancer has led to more targeted therapeutic approaches which focus on blocking, bypassing, or reregulating aberrant pathways, rather than nonspecific killing of cancer cells.

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