Cancer isn’t just one disease–it’s a complex collection of over 100 different conditions, all sharing a set of defining biological traits. Whether it’s lung, breast, colon, or prostate cancer, these diseases behave in remarkably similar ways at the cellular level. So, what gives cancer its edge? What makes it grow uncontrollably, spread across the body, and defy treatment?
In the year 2000, a revolutionary shift occurred in how we think about cancer. A seminal paper by Douglas Hanahan and Robert Weinberg distilled decades of research into a unified biological model. Instead of viewing cancer as a chaotic collection of diseases, Hanahan and Weinberg proposed that all tumors, despite their diversity, share core biological capabilities that enable them to grow, survive, and spread. This new framework, called “The Hallmarks of Cancer”, gave cancer biology a common language.
Their 2000 paper in Cell became one of the most cited works in biomedical science, and for good reason. It distilled the bewildering complexity of cancer into six essential features. Two decades later, this list has expanded and evolved to reflect new discoveries.
Today, these hallmarks are not just a teaching tool. They are a guiding map for cancer research, drug development, and personalized medicine.
What Are the Hallmarks of Cancer?
At its core, cancer is a disease of disrupted cellular regulation. The Hallmarks framework organizes this disruption into a set of enabling traits that allow normal cells to become malignant.
Originally six, the hallmarks have expanded to include additional emerging features and enabling characteristics:
Original Hallmarks (2000)
- Sustaining Proliferative Signaling
- Evading Growth Suppressors
- Resisting Cell Death
- Enabling Replicative Immortality
- Inducing Angiogenesis
- Activating Invasion and Metastasis
Enabling Characteristics of Tumorigenesis
Beyond the core six hallmarks, Hanahan and Weinberg also identified two enabling characteristics that make these traits possible. These features don’t directly drive cancer but set the stage for its development and progression:
• Genome instability and mutation
• Tumor-promoting inflammation
Expanded Hallmarks (2011 Update)
Hanahan and Weinberg updated their framework to include:
- Reprogramming Energy Metabolism
- Evading Immune Destruction
New Dimensions (2022 Update)
Hanahan’s 2022 Cancer Discovery update introduced four emerging hallmarks and enabling factors that emphasize the interplay of genetics, cell biology, and the microenvironment:
- Phenotypic Plasticity
- Non-mutational Epigenetic Reprogramming
- Polymorphic Microbiomes
- Senescent Cells
This review will explore these hallmarks, illustrating how they contribute to tumor development and how each has influenced cancer research and therapy.
Sustaining Proliferative Signaling
Normal cells regulate growth through tightly controlled signals–chemical messages from other cells or hormones that instruct them to divide. Cancer cells, on the other hand, become self-sufficient. They either generate their own growth signals or hijack the signaling systems of their environment.
Tumors may overproduce growth factors (e.g., EGF), mutate receptors (e.g., EGFR), or activate downstream pathways (e.g., RAS-RAF-MEK). This unchecked signaling drives relentless cell division.
Evading Growth Suppressors
While normal cells have built-in brakes to control growth, cancer cells learn to cut the brakes.
Tumor suppressor genes like TP53 (p53) and RB1 usually monitor DNA damage and halt division if something goes wrong. But in cancer, these protective mechanisms are often inactivated. Without these brakes, cancer cells barrel ahead unchecked, even with damaged DNA.
Resisting Cell Death
Our bodies are smart enough to remove faulty or dangerous cells through a process called apoptosis (programmed cell death). Cancer cells, however, learn how to dodge this fate.
They either silence the death signals or boost survival proteins like BCL-2, allowing them to survive longer than they should. This resistance makes tumors more aggressive and harder to treat.
Enabling Replicative Immortality
Normal cells can only divide a certain number of times before aging and dying–a built-in limit known as the Hayflick limit. Cancer cells bypass this limit. They activate an enzyme called telomerase, which rebuilds telomeres–the protective caps at the ends of chromosomes.
This gives cancer cells a kind of cellular immortality, allowing endless divisions. Telomerase inhibitors are under investigation as anti-cancer therapies.
Inducing Angiogenesis
Tumors need nutrients and oxygen to grow beyond a tiny cluster of cells. To achieve this, they hijack the body’s blood vessel network by triggering angiogenesis–the formation of new blood vessels.
Cancer cells release signals like VEGF (vascular endothelial growth factor) to attract new vessels, ensuring a steady supply of nutrients for their expansion.
Activating Invasion and Metastasis
The most deadly feature of cancer is its ability to spread, or metastasize, to distant parts of the body.
To do this, cancer cells break through tissue barriers, travel through the bloodstream or lymphatic system, and colonize new organs. This transition from a local to a systemic disease makes treatment far more difficult.
Genome Instability and Mutation
Cancer cells often have unstable genomes. They accumulate mutations rapidly, affecting genes that control growth, repair, and death. This instability provides the raw material for evolution within the tumor, allowing it to adapt to treatments and evade the immune system.
Tumor-Promoting Inflammation
Chronic inflammation is a double-edged sword. While it’s part of the body’s healing process, persistent inflammation can promote cancer by supplying growth signals, survival factors, and even enzymes that help break down tissue for invasion.
Deregulating Cellular Energetics
Normal cells use oxygen to efficiently produce energy. Cancer cells often switch to a less efficient method known as aerobic glycolysis, or the Warburg effect. This allows them to fuel rapid growth, even in oxygen-poor environments, and build the building blocks needed for cell division.
Avoiding Immune Destruction
One of the immune system’s key roles is to detect and destroy abnormal cells. The immune system can recognize and destroy tumor cells, but cancers evolve to avoid this.
Cancer cells develop stealth tactics, including downregulating antigens and creating an immunosuppressive environment to hide from attack.
Non-mutational Epigenetic Reprogramming
Not all cancer changes are genetic. Some are epigenetic–heritable changes in gene expression without changing the DNA code. Cancer cells use these to rewire their behavior, often reversibly, aiding survival and metastasis.
Polymorphic Microbiomes
The microbes living in and around tumors can influence cancer progression, immune response, and even treatment outcomes. Understanding the tumor microbiome is opening new frontiers in cancer therapy.
Senescent Cells
Senescence is a state where cells stop dividing but don’t die. While senescence halts damaged cells from dividing, senescent cells can release pro-tumorigenic factors known as the senescence-associated secretory phenotype (SASP).
These result in harmful signals, promoting inflammation, tissue damage, and even tumor growth in the surrounding area. Senolytic drugs are being developed to eliminate these cells.
Phenotypic Plasticity
Cancer cells can shift between different cell states (like changing shape or function) to survive stress or treatment. This plasticity helps them resist drugs and adapt to a hostile environment, thereby complicating treatment and supporting recurrence. New strategies are focused on stabilizing cancer cell identity to prevent escape.
Hallmarks in Clinical Practice: From Concept to Care
The Hallmarks of Cancer are not just theoretical–they shape diagnostics, therapeutics, and patient management.
Many modern cancer therapies are designed to target specific hallmarks. For example:
• Anti-angiogenic drugs like bevacizumab block new blood vessel formation.
• Immune checkpoint inhibitors like nivolumab and pembrolizumab reactivate immune attacks on cancer.
• PARP inhibitors exploit genome instability to selectively kill cancer cells with DNA repair defects.
• Targeted therapies like EGFR or HER2 inhibitors aim at specific proliferative signals.
In precision oncology, knowing which hallmarks dominate in a particular cancer type or patient can help tailor therapies, avoid unnecessary treatments, and improve outcomes.
Ethical Considerations and Challenges
As we unravel more hallmarks, we face new ethical and scientific challenges:
• Equity in Access: Advanced diagnostics and therapies often remain out of reach for patients in low-resource settings.
• Tumor Resistance: Cancer can evolve to bypass blocked hallmarks, demanding constant innovation.
• Informed Consent: As genomic and microbiome testing become common, the ethical use of patient data is vital.
Precision oncology demands not only innovation but also equity, responsibility, and humility.
Conclusion: A Living Framework for a Moving Target
The Hallmarks of Cancer provide a powerful lens through which to understand one of medicine’s most complex enemies. By breaking down cancer into its core behaviors, researchers and clinicians can better predict how it will act and how to fight it.
As we uncover more about cancer’s molecular tricks, this framework will continue to evolve. But at its heart, the hallmarks remain a map–a guide to understanding how cancer thrives and how we can stop it.
References
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011.
Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022.
Weinberg RA. The Biology of Cancer. 2nd ed. New York: Garland Science; 2013.
