In 2000, Douglas Hanahan (Seattle, USA, 74 years old) published with Robert Weinberg The Hallmarks of Cancer (The hallmarks of cancer), one of the most influential articles in the history of research on the disease. The two researchers met at a conference in Hawaii and agreed on the need to tackle a monumental task: making sense of the overwhelming complexity of the hundreds of diseases we refer to with a single word.
“There was too much complexity and no clarity, variable responses to therapy and a real deluge of data that describes characteristics of different tumors,” explains Hananhan in a talk with EL PAÍS by videoconference from Lausanne, where he is director emeritus of the Swiss Experimental Cancer Research Institute at the EPFL (École Polytechnique Fédérale de Lausanne). “And so we began to work on the idea that, perhaps, there were some underlying principles that explain this elusive diversity,” he recalls.
In its first synthesis, which has been updated and has just been published its latest version in the magazine CellHanahan and Weinberg described groups of rogue cells that do not respect the exquisite rules that maintain harmony among the organism’s millions of cells and escape the security systems that attempt to maintain order. They found six distinctive characteristics among these cells that do not respect the rules about when to divide, when to stop, when to die and how to cooperate with others so that the organs function.
The first characteristic is that, unlike normal cells, which only divide when the body asks them to, cancer cells proliferate whenever they want and without end. The second trait is that they are capable of evading the molecular brakes that stop this proliferation when there is no longer space to grow or food to do so. The third is that they resist programmed cell death, which normally forces damaged cells to commit suicide. The fourth superpower is that they are practically immortal. Normal cells have a limit of divisions, but cancer cells can divide infinitely while keeping their chromosomes young. The fifth distinctive feature is the ability to access the body’s blood vessels or create new ones to access the oxygen and nutrients necessary to sustain its uncontrolled growth. And finally, the ability to travel to other tissues and colonize them, without respecting their rightful place in the body, as healthy cells do.
In a 2011 review, other features were added, such as evasion of the immune system, which that same year coincided with the appearance of the first immunotherapeutic drugs, which have revolutionized cancer treatment, or an enabling element, such as chronic inflammation. In 2022, other features were added, such as the ability of cells to change their identity and adapt to medications, or to recruit and reprogram normal cells and turn them into accomplices in the rebels’ crime.
Ask. Has the complexity of cancer that you wanted to address in your first article become more manageable in the last 25 years or does the information accumulated in that time make its understanding even more difficult?
Answer. The concept of hallmarks is a way of rationalizing the complexity of cancer and realizing that there are a number of barriers and obstacles that the body puts in place to prevent things like cancer from happening. In symptomatic tumors we see outlaw organs that have learned to evade all these protective mechanisms. This has been very valuable, but we cannot explain the underlying complexity of why different tumors use such diverse mechanisms and have such different characteristics.
P. In total, there are many distinctive capabilities of tumors, but I suppose that the weight of each trait is different in each type of tumor and, as they describe in their articles, the capabilities are activated at different times in the process, and will be different in each individual. Is there a way to know the weight that should be given to each distinctive characteristic, at each moment in the evolution of the disease and in each individual, to fine-tune the treatment?
R. That’s a big question for the future. It is very clear that even if you need these different capabilities, they can arise at different times during the development and progression of an individual tumor, even within patients with exactly the same type of tumor. Not everything is strictly linear. But, first of all, continuous proliferation is really the underlying characteristic of cancer, which differentiates these diseases from others such as neurodegenerative diseases, which do not have that proliferative expansion.
Beyond that, the question is: what distinctive features do they acquire, when, how important are they at different stages of tumor development and tumor progression and responses to therapy?
P. And is that knowledge already used with patients in hospitals?
R. The sequential acquisition of these distinctive capabilities is something we noted from the beginning, and there are drugs being developed against virtually all of these capabilities, but the decision of which drug to use or when remains very empirical.
P. Are there some distinguishing characteristics that have been easier to attack than others?
R. In 2011, we noted that virtually all of them could be attacked. Approximately half of them have clinically validated drugs. In others, there are drugs that have been tested in animal models, but have not been approved to treat patients.
P. For this challenge, do you think that, for example, the power of technologies such as artificial intelligence can be useful to use your framework to generate solutions for those suffering from cancer?
R. The goal is to be able to interrogate tumors from individual patients, to identify which hallmarks of cancer are most important in that specific patient and at a given time in the disease. This information would allow us to decide which are the best therapeutic targets and, therefore, which drugs could be most effective.
In this context, I suggest that so-called digital pathology—which analyzes patient biopsies using machine learning and artificial intelligence—is going to provide numerous new ideas about what distinctive characteristics are really operative in each tumor.
Looking ahead, this opens up a huge opportunity. Not only from classic tissue biopsies, but also through so-called liquid biopsies, in which blood or other body fluids are analyzed for signs of cancer. These techniques could help identify which characteristics are dominant in each case.
Furthermore, imaging technologies—such as MRI, ultrasound, or other modalities—are becoming increasingly sophisticated and based on biological mechanisms, allowing functional, not just anatomical, information to be extracted.
Taken together, all this suggests that in the future it will be possible to recognize the tumor heterogeneity of each patient and, based on it, affirm that this patient is especially dependent on a specific distinctive capacity. Consequently, treatment may be directed at interrupting that specific capacity using drugs designed for this purpose.
P. You are a physicist by training and physicists have been very successful in creating models to understand the complexity of the world around us. But I don’t know if the type of complexity we are talking about is the same as the one that models such as cosmological models try to solve.
R. When we asked the question in 2000, we thought that maybe in 25 years this would be a completely logical system, but I think we are still a long way off.
P. Do you think your idea has been useful in the development of therapies?
R. My hypothesis, for which there are some light signs but not yet spectacular results, is that if these distinctive capabilities are truly independent, it is like a car engine. You have an electrical system, a fuel system, and a system to guide it. And clearly the idea is that if you disrupt each of these abilities separately, it may be more difficult for the tumor to adapt.
The analogy I make is the notion in conventional warfare that you enter by air, by land and by sea. A common feature of all cancer therapies in most patients is that they develop adaptive resistance. The drugs work for a while, and sometimes patients are cured, but most of the time the tumors develop resistance and there is a relapse. One idea I’ve been putting forward for the last decade is that if you target different therapies at the same time, perhaps it would be harder for the tumor to resist, but there aren’t many studies that have tested these therapeutic combinations.
P. But cancer is also a distorted version of our normal self, and many of the processes that are associated with the distinctive characteristics of cancer are capabilities that are necessary for the proper functioning of our body. Is it easy to make these attacks on all of these features without doing much damage to necessary functions?
R. That’s correct, but many of the features are not operational in most cells most of the time, although you clearly have a problem with the therapeutic window. For example, wound healing involves five or six of the nine distinctive abilities, but the key is that wound healing is transient: you get the wound, those activities activate, you heal, and then they go away. In cancer, no. I think targeting these distinctive features is going to be feasible because processes like blood vessel growth or immune response are not happening all the time.
In fact, in the case of the immune system, one of its distinctive characteristics is allowing it to attack and kill tumors. One of the reasons it doesn’t is that the immune system tries to avoid autoimmunity. However, it is clear from these Nobel Prize-winning immune checkpoint inhibitors that it is possible to target tumors, even if that means some side effects to deal with. So this will be, of course, the challenge of any type of monotherapy, but also of any combination therapy that targets several hallmarks: adjusting the drugs, the dosing and the design of the treatment so as not to cause toxicity.
P. There are people who already say that new technological developments will make a cure for cancer possible in the next two decades. Do you think it’s realistic?
R. We are already getting cures in a few patients. The key is going to be having all these new technologies to interrogate tumors, ideally with liquid biopsies, with real biopsies, with non-invasive imaging, so that we can see not only what a tumor looks like before treatment, but how it is behaving during treatment. So if we see that adaptive resistance is kicking in and we can identify the type of adaptive resistance, you could introduce another drug that blocks the adaptive resistance mechanism.
Something that is often said is that what we really need is cancer without disease. We don’t need a total cure. To understand it, most men aged 70 or 80 have prostate carcinomas. There are many histologists who look at a prostate and say, “There is cancer.” But it is contained by all kinds of checks and balances in the prostate and only bursts and escapes in a fraction of individuals. The rest of these men live normal lives and die with “indolent prostate cancer.”
I think it may be that with these capabilities of monitoring how tumors are responding to therapy with increasingly sophisticated technologies, we will actually be able to keep cancer under control to allow people to live normal lives.
I’m not convinced that AI alone will magically cure cancer, but machine learning or AI in combination with digital pathology or non-invasive imaging technologies will make it possible to interrogate tumors at various stages of their progression and tailor therapies.
date:2026-02-13 04:30:00
Worth a look