Cancers are characterized by unregulated cell growth, tissue invasion, and metastasis. A neoplasm is benign when it grows in an unregulated fashion without tissue invasion. The presence of both features is characteristic of malignant neoplasms. Cancers are named based on their origin: those derived from epithelial tissue are called carcinomas, those derived from mesenchymal tissues are sarcomas, and those derived from hematopoietic tissue are leukemias or lymphomas.
Cancers nearly always arise as a consequence of genetic alterations. Choriocarcinoma may be an exception to this rule in that experimental insertion of a choriocarcinoma cell into an animal blastocyst can result in the neoplastic cell giving rise to normal body structures under the inductive influence of the developing embryo. Such an occurrence would be unlikely in the setting of irreversible genetic damage.
Occasional cancers appear to be caused by an alteration in a dominant gene that drives uncontrolled cell proliferation. Examples include chronic myeloid leukemia (abl) and Burkitt's lymphoma (c-myc). The genes that can promote cell growth when altered are often called oncogenes. They were first identified as critical elements of viruses that cause animal tumors; later it was found that the viral genes had normal counterparts with important functions in the cell and had been captured and mutated by viruses as they passed from host to host.
However, the vast majority of human cancers are characterized by multiple genetic abnormalities, each of which contributes to the loss of control of cell proliferation and differentiation and the acquisition of capabilities, such as tissue invasion and angiogenesis. Many cancers go through recognizable steps of progressively more abnormal phenotypes: hyperplasia, to adenoma, to dysplasia, to carcinoma in situ, to invasive cancer (Table 84–1). These properties are not found in the normal adult cell from which the tumor is derived. Indeed, normal cells have a large number of safeguards against uncontrolled proliferation and invasion.
Table 84–1 Phenotypic Characteristics of Malignant Cells
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Table 84–1 Phenotypic Characteristics of Malignant Cells
|Deregulated cell proliferation: Loss of function of negative growth regulators (suppressor oncogenes, i.e., Rb, p53), and increased action of positive growth regulators (oncogenes, i.e., Ras, Myc). Leads to aberrant cell cycle control and includes loss of normal checkpoint responses.|
|Failure to differentiate: Arrest at a stage before terminal differentiation. May retain stem cell properties. (Frequently observed in leukemias due to transcriptional repression of developmental programs by the gene products of chromosomal translocations.)|
|Loss of normal apoptosis pathways: Inactivation of p53, increases in Bcl-2 family members. This defect enhances the survival of cells with oncogenic mutations and genetic instability and allows clonal expansion and diversification within the tumor without activation of physiologic cell death pathways.|
|Genetic instability: Defects in DNA repair pathways leading to either single or oligo-nucleotide mutations (as in microsatellite instability, MIN) or more commonly chromosomal instability (CIN) leading to aneuploidy. Caused by loss of function of p53, BRCA1/2, mismatch repair genes, DNA repair enzymes, and the spindle checkpoint.|
|Loss of replicative senescence: Normal cells stop dividing in vitro after 25–50 population doublings. Arrest is mediated by the Rb, p16INK4a, and p53 pathways. Further replication leads to telomere loss, with crisis. Surviving cells often harbor gross chromosomal abnormalities. Relevance to human in vivo cancer remains uncertain. Many human cancers express telomerase.|
|Increased angiogenesis: Due to increased gene expression of proangiogenic factors (VEGF, FGF, IL-8) by tumor or stromal cells, or loss of negative regulators (endostatin, tumstatin, thrombospondin).|
|Invasion: Loss of cell-cell contacts (gap junctions, cadherins) and increased production of matrix metalloproteinases (MMPs). Often takes the form of epithelial-to-mesenchymal transition (EMT), with anchored epithelial cells becoming more like motile fibroblasts.|
|Metastasis: Spread of tumor cells to lymph nodes or distant tissue sites. Limited by the ability of tumor cells to survive in a foreign environment.|
|Evasion of the immune system: Downregulation of MHC class I and II molecules; induction of T cell tolerance; inhibition of normal dendritic cell and/or T cell function; antigenic loss variants and clonal heterogeneity; increase in regulatory T cells.|
In most organs, only primitive nonfunctional cells are capable of proliferating and the cells lose the capacity to proliferate as they differentiate and acquire functional capability. The expansion of the primitive cells is linked to some functional need in the host through receptors that receive signals from the local environment or through hormonal influences delivered by the vascular supply. In the absence of such signals, the cells are at rest. We have a poor understanding of the signals that keep the primitive cells at rest. These signals, too, must be environmental, based on the observations that a regenerating liver stops growing when it has replaced the portion that has been surgically removed and regenerating bone marrow stops growing when the peripheral blood counts return to normal. Cancer cells clearly have lost responsiveness to such controls and do not recognize when they have overgrown the niche normally occupied by the organ from which they are derived. We know very little about this mechanism of growth regulation.
Normal cells have a number of control mechanisms that are targeted by specific genetic alterations in cancer. The progression of a cell through the cell division cycle is regulated at a number of checkpoints by a wide array of genes. In the first phase, G1, preparations are made to replicate the genetic material. The cell stops before entering the DNA synthesis phase or S phase to take inventory. Are we ready to replicate our DNA? Is the DNA repair machinery in place to fix any mutations that are detected? Are the DNA replicating enzymes available? Is there an adequate supply of nucleotides? Is there sufficient energy? The main brake ...