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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.
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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.
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:
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.
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.
White pinpoints display telomeres in the 46 human chromosomes, shown in blue.
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.
In order to grow unchecked, cancer cells have to develop the ability to multiply without limit. Approximately 85% to 90% of cancer cells achieve this end by upregulating the expression of the enzyme telomerase, which helps to maintain the telomeres and prevent their shortening.
Normal cells must typically reside within 100 μm of a blood vessel in order to obtain necessary oxygen and nutrients. This limits the ability of cells to invade all areas of the body and of tissues to grow beyond a certain size. In order to overcome this issue, cancer cells acquire a fifth hallmark, the ability to stimulate angiogenesis (growth of new blood vessels).
In normal cells, the balance between proangiogenic and antiangiogenic signaling pathways is regulated by an “angiogenic switch,” which is tightly regulated in normal cells so that angiogenesis is only turned on during processes such as wound healing. In contrast, in cancer cells it is almost always turned on, stimulating the growth of new blood vessels and sustaining tumor growth.
Among the best-known proangiogenic pathways is the vascular endothelial growth factor (VEGF) pathway.
The final hallmark is the key to the destructive capability of tumors and is responsible for 90% of all cancer-related deaths. It is also the hallmark of which we currently have the poorest understanding.
Some cancer cells are able to break away from the original tumor, migrate to a new area of the body, and establish a second site of tumor formation (metastasis). In order to do this successfully, among other characteristics, cancer cells have to be able to reduce cell-to-cell adhesion and increase cell motility. The most common alteration in cancer cells resulting in invasion and metastasis is in the tethering protein E-cadherin.
In the past decade there has been a continuing expansion of our anticancer armamentarium. To date, rather than targeting hallmarks as a whole, most new drugs have been developed to target specific proteins within key hallmark-associated signaling pathways.
The most promising advances have come from the development of smallmolecule inhibitors and monoclonal antibodies targeting the tyrosine kinase receptors. These include the EGFR inhibitor gefitinib (Iressa, AstraZeneca) and the HER2 monoclonal antibody trastuzumab (Herceptin, Genentech), which primarily target the hallmark of unrestricted growth.
The first clinical validation that inhibiting a tumor’s blood supply would thwart its growth—the angiogenesis hallmark—came in 2003 when bevacizumab (Avastin, Genentech/Roche), an anti-VEGF monoclonal antibody, proved effective against colorectal cancer. Although the agent has been controversial in the treatment of breast cancer, the drug remains FDA-approved for 4 other cancer types.
Agents targeting VEGF receptors are a robust area of exploration. One prominent example is axitinib (Pfizer Inc), which the FDA is now reviewing as a treatment for renal cell carcinoma.
Drugs in development that focus on the hallmark of unlimited cell division include imetelstat (GRN163L, Geron). The short-chain nucleic acid molecule, currently in phase II clinical trials, has displayed inhibitory activity against telomerase.
Research in the area of the sixth hallmark, invasion and metastasis, has exploded in recent years, and targeted therapies have now begun to emerge. A prime example is inhibitors of the hepatocyte growth factor (HGF) receptor, c-MET, which has a key role in cell motility and invasion. A number of these agents are in development, including tivantinib (ARQ 197, ArQule), currently in the final phase of clinical development for the treatment of non-small cell lung cancer.
Targeting tumor-suppressor proteins, such as p53, has proved much more challenging since they often defy conventional drug development paradigms. However, it has driven innovative new drug design processes and the development of treatments such as vaccines and gene therapy.
In spite of these substantial therapeutic advances, shutting off a single pathway may not be sufficient to halt tumorigenesis, since other pathways may simply take over to drive hallmark acquisition, reflected in the level of resistance to these therapies.
Much research is already focused on the idea of targeting multiple different pathways with combinations of targeted agents. However, we are also beginning to move away from our view of tumors as homogenous collections of cells that are all at the same stage. Different cells within the tumor population may have acquired different hallmarks by separate mechanisms, and therefore co-targeting multiple components of different hallmark processes may also be beneficial.
Another shift that is occurring is the identification of other potential hallmarks; researchers have proposed a number of other characteristics that appear to be common to all tumor cells, and that the 6 hallmarks are not sufficient for tumorigenesis.
Two of the most commonly proposed additional hallmarks are evasion of the immune system (tumors are able to subvert the normal immune response or develop defensive responses to it) and reprogramming of cell metabolism (the so-called Warburg effect, whereby tumors are able to reprogram their glucose metabolism, using glycolysis in the presence of oxygen).
It has also been suggested that there are “enabling characteristics,” which must first occur in order for cancer cells to be able to begin acquiring hallmarks. Most prominent is the development of genomic instability in cancer cells. In normal cells, mutation is a rare event since it is detected by genomic “guardians,” which drive cells to either repair the damage or undergo apoptosis. In order to accumulate mutations, cancer cells must remove these protective mechanisms, allowing the unchecked generation of mutations that drive hallmark acquisition.
The second proposed enabling characteristic is tumor-promoting inflammation. The body’s response to a tumor is to elicit an immune response, causing inflammation. Recently, it has been revealed that cancer cells may use this inflammatory response to their benefit. Persistent inflammation in the surrounding environment inadvertently provides the tumor with a source of growth, survival, and proangiogenic factors, enabling the development of several hallmarks.
The place for hallmarks and their enabling characteristics has led to some debate. Some believe that tumorigenesis is vastly more complex and that there are many more hallmarks than currently described. Others believe that only metastasis is the key defining hallmark of cancer. An example is the importance of altered metabolism. Some researchers believe that our entire way of thinking about cancer is fundamentally flawed, and that instead of viewing cancer as a genetic disease, we should instead be thinking of it as a metabolic disease.
Regardless, a number of new therapies have arisen from our more developed understanding of cancer biology. Increasing appreciation of the role of inflammation and the immune response has led to investigation of anti-inflammatory drugs and the development of vaccines. Currently, cancer vaccines are only effective in the prevention of viral-associated cancer. However, in 2010, the FDA approved the first therapeutic cancer vaccine, sipuleucel-T (Provenge, Dendreon Corporation) for prostate cancer.
Rational approaches to cancer management may also be found in therapies targeting energy metabolism. Preclinical studies are assessing the efficacy of small molecules targeting aerobic glycolysis, including 2-deoxyglucose, lonidamine, and 3-bromopyruvate, as well as glutamine-binding drugs, since glutamine is a major metabolite in many cancers.
Jane de Lartigue, PhD, is a freelance medical writer and editor based in the United Kingdom.