A framework for understanding (and researching) what causes human cancers

(Press-News.org) An enduring challenge for the study of human cancer is just how complex it is: how many different ways there are for cancers to originate, progress, and spread in the people who are diagnosed with them. In a review publishing January 29 in the Cell Press journal Cell, biologist Douglas Hanahan of the Ludwig Institute for Cancer Research in Lausanne, Switzerland, offers a major update to his long-standing framework to help those studying cancer make sense of its remarkable diversity and complexity.

This framework, known as the Hallmarks of Cancer and originally proposed 26 years ago by Hanahan and colleague Robert A. Weinberg of the Ludwig Center at MIT, identified six key changes in cell physiology that were likely to be present in most, if not all, types of human tumors. These “hallmarks” allowed cancers to bypass the cell’s usual defenses against unchecked, malignant growth. The original review and its 2011 update, which expanded the number of hallmarks from six to eight, have together been cited over 75,000 times in the scientific literature.

But while the Hallmarks of Cancer has played a critical role in shaping how we understand human cancers today, several amendments and additions made over the years to reflect the knowledge and data produced by the evolving field of cancer research have also made the framework much more complex.

“Its attractive simplicity has arguably become more complicated,” writes Hanahan.

In the new review, Hanahan proposes an updated way of thinking about the hallmarks, as just one of four distinct but interconnected dimensions that underpin how cancers arise and evolve. In addition to those acquired changes in cell functioning—such as insensitivity to anti-growth signals and the ability to continue producing new blood vessels—that are present in all tumors, Hanahan also proposes the following dimensions:

Enabling characteristics such as genome instability, epigenetic reprogramming (where mutations don’t exist), and tumor-promoting inflammation, which facilitate the acquisition of the hallmarks Classes of normal cells such as fibroblasts and immune cells that can be recruited and reprogrammed as “accessories to the crime” to carry and perpetuate hallmark changes in cancer cells Systemic factors such as aging and obesity that Hanahan calls “clouds of complexity” because they interact with cancer throughout its progression and offer additional challenges and opportunities for patient treatment and quality of life The review explores each of these dimensions in detail, synthesizing recent research on each of the nine cancer cell hallmarks, five enabling characteristics, seven classes of hallmark-facilitating cells, and two examples of hallmark-influencing systemic interactions. In addition, Hanahan offers a hypothesis for further exploration: that treatments developed and targeted to attack multiple hallmark capabilities of cancer cells at once could be more effective long term than many of our current treatments.

“The conceptual premise set forward in January of the year 2000 has endured, remarkably and unexpectedly, for twenty-six years,” writes Hanahan in closing, “namely that there is a logical underpinning to the complexity and diversity of human cancer.” This new framework, he says, “hopefully restores some of that conceptual clarity.”

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This work was supported by the Ludwig Institute for Cancer Research (New York, NY) and the Berta Kamprad Foundation (Älmhult, SE).

Cell, Douglas Hanahan, “Hallmarks of Cancer – then and now, and beyond” https://www.cell.com/cell/fulltext/S0092-8674(25)01498-9

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