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. The multiple mechanisms may be responsible for the relatively rare occurrence of cancer during an average human lifetime.

Self-sufficiency in growth signals

Normal cells require mitogenic growth signals (GS), transmitted by transmembrane receptors. The signaling molecules can be:

• Diffusible growth factors
• ECM components
• Cell-to-cell adhesion/interaction molecules (i.e. integrins)

Many oncogenes mimic normal growth signaling. The tumor cells have greatly reduced dependence on exogenous growth stimulation - generate many of their own growth signals - hence disrupting a critically important homeostatic mechanism. Many dominant oncogenes are found to modulate this.

3 common strategies:

• Alteration of extracellular growth signals
• Alteration of transcellular transducers/receptors
• Alteration of intracellular circuits translating those signals

Whiel most soluble mitogenic growth factors are made by one cell type to stimulate another (heterotypic signaling), cancer cells can synthesize the growth factors to which they are responsive - positive feedback or autocrine stimulation - and obviates dependence on GFs from other cells within the tissue.