Genetic evolution shaped by darwinian selection can explain the two most pernicious properties of cancers: the tendency over time for cancers to become both more aggressive and less responsive to therapy. Thus, genetic heterogeneity has implications not only for cancer progression but also for its response to therapy. Experience has shown that when tumors recur after chemotherapy, the recurrent tumor is almost always resistant to the original drug regimen if it is given again. Experimental data suggest that this acquired resistance stems from the outgrowth of subclones that have, by chance, mutations (or epigenetic alterations) that impart drug resistance.
This overview serves as background for a more detailed consideration of the molecular pathogenesis of cancer. As mentioned earlier, bona fide cancer genes number in the hundreds, at a minimum. While it is traditional to describe the function of cancer genes one gene at a time, the blizzard of mutated genes emerging from the sequencing of cancer genomes has blanketed the landscape and revealed the limitations of trying to grasp the fundamental properties of cancer, gene by gene. A much more tractable and conceptually satisfying way to think about the biology of cancer is to consider the common phenotypic and http://ebooksmedicine.net
Accumulation of driver and passenger mutations
Carcinogen-induced Additional driver Additional mutations, mutation
Emergence of subclones Diagnosis
Normal Initiated precursor with Founding
Fig. 6.16 Developmentofcancerthroughstepwiseaccumulationofcomplementarydrivermutations.Theorderinwhichvariousdrivermutationsoccurisusuallyunknownandmayvaryfromtumortotumor.
biological properties of cancer cells. It appears that all cancers display eight fundamental changes in cell physiology, which are considered the hallmarks of cancer.
These changes are illustrated in
Fig. 6.17 and consist of the following:
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Evasion of immune surveillance
The acquisition of the genetic and epigenetic alterations that confer these hallmarks may be accelerated by cancer-promoting inflammation and by genomic instability. These are considered enabling characteristics because they promote cellular transformation and subsequent tumor progression.
Mutations in genes that regulate some or all of these cellular traits are seen in every cancer; accordingly, these traits form the basis of the following discussion of the molecular origins of cancer. Of note, by convention, gene symbols are italicized but their protein products are not (e.g., RB gene and RB protein, TP53 and p53, MYC and MYC).
The self-sufficiency in growth that characterizes cancer cells generally stems from gain-of-function mutations that convert proto-oncogenes to oncogenes. Oncogenes encode proteins called oncoproteins that promote cell growth, even in the absence of normal growth-promoting signals. To appreciate how oncogenes drive inappropriate cell growth, it is helpful to review briefly the sequence of events that characterize normal cell proliferation (introduced in Chapter 1). Under physiologic conditions, cell proliferation can be readily resolved into the following steps: 1.
Binding of a growth factor to its specific receptor on the cell membrane 2.
Transient and limited activation of the growth factor receptor, which in turn activates several signaltransducing proteins on the inner leaflet of the plasma membrane 3.
Transmission of the transduced signal across the cytosol to the nucleus by second messengers or a cascade of signal transduction molecules 4.
Induction and activation of nuclear regulatory factors that initiate and regulate DNA transcription and the biosynthesis of other cellular components that are needed for cell division, such as organelles, membrane components, and ribosomes 5.
Entry and progression of the cell into the cell cycle, resulting ultimately in cell division
Fig. 6.17 Eightcancerhallmarksandtwoenablingfactors(genomicinstabilityandtumor-promotinginflammation).Mostcancercellsacquirethesepropertiesduringtheirdevelopment,typicallyduetomutationsincriticalgenes.(From Hanahan D,Weinberg RA: Hallmarks of cancer: the next generation. Cell144:646, 2011.)