The Hallmarks of Cancer
Authors: Douglas Hanahan and Robert A. Weinberg
Published: Cell Vol 100 (2000), pages 57-70
Introduction
Cancer genes can be classified into two: the oncogenes with dominant gain of function; and tumor suppressor genes with recessive loss of function. In this paper, the authors described the rules that govern the transformation of cells into malignant states - acquired capabilities - shared across different types of cancers. Virtually, all mammalian cells carry similar molecular machinery that dictates cellular behaviors.
Tumorigenesis in humans is a multistep process, which reflects genetic alterations. Many cancers are diagnosed with age-dependent incidence that implicates 4-7 rate-limiting stochastic events. Lesions represents intermediate steps in which cells evolve toward malignancy. Genomes of tumor cells are invariably altered at multiple sites (i.e. lesions, point mutations, changes in chromosome complement). The transformation process is formally analogous to Darwinian evolution.
An Enumeration of the Traits
The main problem in cancer is that cancer cells have defects in regulatory circuits that govern normal cell proliferation and homeostasis. The large variety of types of cancers raises a number of questions:
- How many distinct regulatory circuits within each type of target cell must be disrupted for the cell to become cancerous?
- Does the same set of circuits suffer disruption in other types of cancer cells in the body?
- Which of the circuits operate cell-autonomously? Which are coupled to signals from environment?
- Can cancer-associated genes be related to these regulatory circuits?
The authors hypothesized that the cancer cell genotypes are the manifestation of 6 essential alterations shared among tumors
- Self-sufficiency in growth signals
- Insensitivity to growth-inhibitory signals
- Evasion of apoptosis
- Limitless replicative potential
- Sustained angiogenesis
- Tissue invasion and metastasis
Each represents successful breaching of the defense mechanism
