Most cited Cell Article of All Time, “Hallmarks of Cancer” Gets an Update

“Hallmarks of Cancer”, published in the journal Cell in 2000, provided a conceptual framework for the evolution of cancer as well as an all-encompassing review of the cancer field to date. Douglas Hanahan (UCSF) and Robert A. Weinberg (MIT) described the process of tumorigenesis, and proposed six hallmarks that “constitute an organizing principle that provides a logical framework for understanding the remarkable diversity of neoplastic disease”. The authors described the concepts of cancer pathogenesis, emphasizing that “recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.”

Apoptosis inducing factor; Source: Wikimedia Commons user pymol

The original hallmarks: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis are six biological processes necessary for tumor development and metastasis.

Next-generation Hallmarks of Cancer

Published in the March 4, 2011 issue of Cell, the newly updated version includes two emerging hallmarks based on progress within the last decade-reprogramming of energy metabolism and evading immune destruction (DOI 10.1016/j.cell.2011.02.013). The authors also describe two hallmarks that enable tumorigenesis-genomic instability and inflammation. The review also processes the findings in cancer research since the turn of the 20th century to update the original six commonalities of cancer evolution.

One key development has been the concept of a complex tumor landscape, a tissue composed of a spectrum of cell types that interact with surrounding normal tissue that forms a “tumor microenvironment” that facilitates tumor growth. The emerging overview highlights both the progress made and opens up countless new questions about the complicated path of tumor formation.  The following sections summarize the key concepts of the hallmarks of cancer and provide a summary of the novel developments elucidated over the last decade, since the publication of the original review.

Sustaining Proliferative Signaling

While normal tissues prudently control both cell division rates and cell size, a key requirement of cancerous cells is their ability to allow uninhibited cell proliferation. Cancer genome sequencing in the last decade has identified the ways that cancer cells activate signaling pathways that allow this unhindered growth. For example, we now know that ~40% of melanomas harbor a somatic mutation in the BRAF gene that is part of a MAP kinase growth-signaling pathway. Additionally, studies have now shown that cancer cells have acquired alterations in negative feedback loops that normally curb cell proliferation signaling. The authors speculate that alterations in these pathways will be found in a majority of cancers and may contribute to the adaptive resistance seen in tumors exposed to treatments that target the mitogenic proliferation signaling pathways. A third novel concept is the observation that increasing proliferative signaling results in a threshold at which the cell goes into a senescent (dormant) state, discounting the hypothesis that there is a linear relationship between proliferative signaling and growth rate. 

Evading Growth Suppressors

Cancer cells acquire mutations in tumor suppressors, proteins that function to negatively regulate proliferation. A classic example is the retinoblastoma-associated (RB) protein. The idea that contact inhibition likely results from tumor suppressor function and that cancer cells lose this inhibition was known for some time. Only recently, however, have some of the mechanisms by which this inhibition occurs began to become clear.

Resisting Cell Death

Apoptosis is a biological mechanism that occurs in response to cellular stresses and naturally curbs the tumorigenic process. Many signals produced by cancer cells, including those indicating DNA damage and elevated levels of proliferative signaling, trigger apoptosis. Cancer cells have been shown to evade cell death via dysfunctional sensors of these signals or errors within the apoptotic pathway itself. Autophagy, another pathway that's activated by stress signals has been found to be activated in cancer cells. Common regulatory mechanisms of both apoptosis and autophagy have now been elucidated as well as mechanisms that induce autophagy, and therefore survival, in cancer cells that include cytotoxic drugs and radiotherapy. Necrosis, yet a third pathway of cell death, has now been shown as being genetically controlled under certain circumstances. Furthermore, the release of cell contents results in a proinflammatory signal that results in inflammation, fostering tumor promotion.  

Enabling Replicative Immortality

Normal cells go through a limited number of cell divisions before they undergo senescence and subsequent crisis and cell death. Conversely, cancer cells acquire the ability to undergo unlimited cell divisions, essentially becoming immortal. Telomeres provide a sort of accounting method for measuring cell life span. Telomeres shorten with every cell division, until a critically short length triggers cell death. Approximately 90% of immortalized cells, including cancers, have the ability to increase their telomere length due to a mutation in telomerase. A view is starting to emerge, from both human malignancy and mouse models, that delayed activation of telomerase fosters an environment in which premalignant cells acquire mutations that promote tumorigenesis. Subsequently, telomerase activation stabilizes these cells and results in replicative immortality. Interestingly, a non-canonical role for telomerase in cell proliferation, but not telomere maintenance, has also emerged although the implications for this function in tumorigenesis are not yet clear.

Inducing Angiogenesis

New vasculature is necessary to provide tumors with nutrients and metabolic waste evacuation. The normally dormant neovasculature process is switched on relatively early during invasive tumor development. In the past decade, researchers have found that different types of tumors exhibit quite different neovasculature patterns, from highly dense vessel formations to hypovascularized tumors. Additionally, cells originating in bone marrow are now known to play an important role in angiogenesis associated with tumor growth.

Activating Invasion and Metastasis

The process of invasion and metastasis were presumed to be a multi-step cascade, but the underlying mechanisms were not yet characterized in 2000. Since then, important aspects of the process have been carved out but many questions remain. For example, the “epithelial mesenchymal transition" is a developmental regulatory program that is now implicated in the progression of epithelial cells to metastatic cells able to invade other tissues and disseminate. Communication between cancer cells and their microenvironment of non-cancerous cells is also seen as important for metastasis. Based on current data of different modes of invasion, it is probably true that different tumor types utilize different invasion techniques.

Enabling Characteristics and Emerging Hallmarks

Hanahan and Weinberg have added two characteristics that confer the “functional capabilities that allow cancer cells to survive, proliferate, and disseminate." The first characteristic is genomic instability, which facilitates a higher than normal mutation rate and aberrations in the genome. The second is the immune system’s creation of an inflammatory state. Certain tumors are highly infiltrated with the cells of the immune system and a picture has emerged whereby immune cells promote tumor progression.

The authors include two hallmarks that may emerge as very important and part of the core cancer framework they originally created. One is the support of proliferation via reprogramming of energy metabolism with cells. A second is the ability of cancer cells to escape the surveillance and attack by the body’s immune system. This latter concept is particularly important in light of emerging treatments that aim to harness the strength of the immune system to attack tumors.

Translation of Cancer Hallmarks into Treatments

Mechanism-based treatments are emerging from the last three decades of research on the fundamental characteristics of tumor evolution. Targeted therapies, the authors point out, can be categorized by their effects on one of more cancer hallmarks and their efficacy is a validation of the importance of a specific capability of a tumor.  Most drug development has been directed toward specific molecular targets. However, the result of these specific treatments is eventual cancer relapse. “One interpretation of this history, supported by growing experimental
evidence, is that each of the core hallmark capabilities is regulated by partially redundant signaling pathways.” Therefore, the authors argue, inhibition of a single key pathway does not inhibit the “hallmark capability” and allows adaptation via mutation, changes of the microenvironment, or epigenetic reprogramming. Prevention of resistance should be prevented by targeting all of the pathways within a capability. Cancer cells can also adapt to a treatment by decreasing their reliance on a specific hallmark that the treatment targets.

Hanahan and Weinberg emphasize the potential to uncover many of the underlying mechanisms within each hallmark in the foreseeable future. Having established a conceptual framework by which to organize the myriad of scientific cancer data we have accrued, they leave the reader with an enhanced version of their powerful tool.