What Turns a Good Cell Bad? Exploiting the Hallmarks of Cancerous Cells

Jane de Lartigue, PhD
Published: Thursday, Feb 02, 2012

Strategies Targeting the Hallmarks of Cancer

Strategies Targeting the Hallmarks of Cancer Click to enlarge.

This figure illustrates some of the many approaches employed in developing therapeutics targeted to the known and emerging hallmarks of cancer.

EGFR indicates epidermal growth factor receptor; CTLA4, cytotoxic T lymphocyte-associated antigen 4; mAb, monoclonal antibody; HGF, hepatocyte growth factor; VEGF, vascular endothelial growth factor; PARP, poly-(ADP ribose) polymerase.

Source: Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674. Reprinted with permission.

It has been more than a decade since Douglas Hanahan, PhD, and Robert A. Weinberg, PhD, published their seminal review of cancer, which outlined “six essential alterations in cell physiology” that govern the transformation of normal cells into malignant tumors. Since then, it has become one of the most cited articles of all time, reflecting the widespread acceptance of these “hallmarks” of cancer.

In light of the recently published update of this review, we reflect on our current understanding of the biology of tumors and the signaling pathways that cancer cells use to achieve these hallmarks, whether the hallmarks are still widely applicable, and how they guide cancer research and therapeutic strategies.

Defining 6 Hallmarks of Cancer

Hanahan and Weinberg initially outlined 6 hallmarks that they believed were essential to the transformation of normal cells into malignant cancer cells in most, if not all, human cancers:

1. Self-Sustained Growth

2. Avoiding Growth Inhibition

Normal cells need to receive growth signals before they can begin to grow and divide, and their growth is kept in check by a number of antigrowth signals. Cancer cells acquire the ability to essentially drive through a red light, bypassing the requirement for growth signals and avoiding antigrowth signals; this forms the basis of the first 2 hallmarks.

There are several ways in which cancer cells can stimulate their own growth. They can alter extracellular growth signals, either by stimulating the normal cells in their surrounding environment to produce growth factors, or by producing growth factors to which they themselves are responsive.

They can modify the expression of the cell surface receptors that transduce these growth signals, the most prominent example being the tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), both commonly overexpressed in many different kinds of cancer.

Finally, they can alter the intracellular signaling networks that translate growth signals into action, via overexpression of components of pathways that stimulate growth or defects in feedback mechanisms that attenuate growth signaling. The PI3K/Akt and Ras/Raf/mitogen-activated protein kinase (MAPK) pathways play a key role in this respect, reflected in the fact that the PI3K/Akt pathway is one of the most perturbed in human cancer, and that a quarter of all cancers have Ras alterations.

Antigrowth signals are primarily channeled through 2 “gatekeeper” proteins: retinoblastoma protein (pRb) and p53. Cancer cells further promote their own growth by disrupting the function of these 2 proteins, which in normal cells control transcription factors that regulate the expression of growth-related genes.

3. Avoiding Death

Efficient disposal of defective cells through programmed cell death (apoptosis) is an integral part of the normal function of multicellular organisms.

The cellular machinery that coordinates apoptosis is divided into 2 classes: sensors that detect “survival” and “death” signals in the environment (including the insulin-like growth factor receptor [IGFR] and the FAS receptor) and effectors that either elicit or suppress apoptosis in response to those signals (including p53 and members of the Bcl-2 family).

Cancer cells acquire the ability to avoid apoptosis, the third hallmark, in a number of ways. The most common is a loss of p53, which normally initiates apoptosis, and is lost in more than 50% of human cancers. Other mechanisms include increased expression of antiapoptotic Bcl-2 family members or of the IGFR, and decreased expression of the FAS receptor.

telomeres in the 46 human

White pinpoints display telomeres in the 46 human chromosomes, shown in blue.

4. Limitless Division

Surprisingly, acquiring these first 3 hallmarks is not sufficient for unlimited cell growth within tumors. Normal cells also have a finite potential to divide. After a certain number of divisions, shortening of the telomeres, which protect the ends of the chromosomes, prevents the cell from further dividing to avoid chromosomal damage.

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