The “hallmarks of cancer” provides a framework for understanding the complex disease of cancer. This set of shared biological characteristics explains how normal cells can transform into malignant tumors. Proposed by scientists Douglas Hanahan and Robert Weinberg in 2000, this model simplifies the complexities of how cancer develops and progresses. Their work established an organizing principle that has since guided research and the development of new treatments, outlining the common capabilities that cancers acquire to survive.
The Core Principles of Uncontrolled Growth
A defining feature of a cancer cell is its ability to sustain chronic proliferation. Normal cells require external signals to grow and divide, a tightly regulated process. Cancer cells, however, can generate their own growth signals, creating a constant “go” command for cell division. This is comparable to a car with a permanently stuck accelerator pedal, leading to unchecked growth. This capability arises from mutations in genes known as proto-oncogenes, such as the RAS gene family, which then become oncogenes.
In concert with promoting their own growth, cancer cells must also bypass the “stop” signals that normally halt cell division. Healthy cells respond to antigrowth signals that prevent overcrowding, but cancer cells learn to ignore these commands. This is analogous to cutting the brake lines of an accelerating car. This defiance is achieved by inactivating tumor suppressor genes, the gatekeepers of cell division. The p53 tumor suppressor gene is a prominent example; when it is mutated, a cell loses a primary mechanism for stopping proliferation.
This dual strategy of stimulating their own growth while ignoring signals to stop allows cancer cells to break free from the normal constraints on cell division. By overcoming these anticancer defense mechanisms, malignant cells uncouple their growth program from the needs of the organism. This liberates them to multiply uncontrollably, laying the groundwork for tumor formation.
Achieving Immortality and Spread
Beyond uncontrolled growth, cancer cells must survive conditions that would normally trigger their demise. One of the body’s safety mechanisms is programmed cell death, or apoptosis, which eliminates damaged or unneeded cells. Cancer cells, however, develop the ability to resist apoptosis, disabling their own self-destruct mechanism. They achieve this by altering signaling pathways, such as through mutations that increase the production of anti-apoptotic proteins like BCL-2.
Normal human cells also have a built-in limit to how many times they can divide, a process linked to structures called telomeres. Telomeres are protective caps at the ends of chromosomes that shorten with each cell division. Once they become too short, the cell enters a non-dividing state or triggers apoptosis. Cancer cells circumvent this by activating an enzyme called telomerase, which rebuilds the telomeres. This gives them replicative immortality, allowing for the limitless divisions required to form a large tumor.
A devastating capability is the ability to invade nearby tissues and metastasize to distant parts of the body. This process begins with cancer cells breaking away from their original tumor. They then penetrate surrounding tissues, enter the bloodstream or lymphatic system, and travel to new locations. Upon arrival, they establish a new tumor, or metastasis, in a different organ. This ability to spread is responsible for the vast majority of cancer-related deaths.
Sustaining the Tumor Microenvironment
For a tumor to grow beyond a small mass, it must secure its own supply of nutrients and oxygen. To do this, cancer cells induce the formation of new blood vessels, a process known as angiogenesis. A growing tumor sends chemical signals that encourage nearby blood vessels to sprout new branches into the tumor mass. These new vessels function like highways, delivering the oxygen and nutrients to fuel the tumor’s expansion. Without this blood supply, a tumor would be unable to grow larger than a few millimeters.
Cancer cells also rewire their internal metabolism to support their high rate of proliferation. This metabolic reprogramming, called the Warburg effect, involves a shift in how cells produce energy. Even when oxygen is plentiful, cancer cells favor a less efficient but much faster method of energy production known as aerobic glycolysis. This provides the building blocks—such as proteins, lipids, and DNA—needed to create new cells quickly. This altered metabolism is an active strategy to sustain growth.
The area immediately surrounding a tumor, the tumor microenvironment, is a complex ecosystem that cancer cells manipulate for their benefit. In addition to inducing blood vessel growth, tumors recruit and corrupt various normal cells. These recruited cells can help by providing growth factors, suppressing immune responses, and remodeling the physical environment to make invasion easier. By co-opting their local environment, tumors create a supportive niche that sustains their growth and survival.
Evading Defenses and Promoting Instability
The human immune system is equipped to recognize and eliminate abnormal cells, including cancerous ones. However, successful tumors develop strategies to avoid being destroyed by immune cells. They can make themselves less visible to the immune system by reducing identifying markers on their surface. Additionally, cancer cells can produce signals that actively suppress the immune response, deactivating the T-cells that would otherwise attack them. This evasion of immune destruction is a necessary step in a tumor’s development.
Fueling the acquisition of these capabilities is a characteristic of cancer cells: genomic instability. Cancer cells have a high rate of mutation, meaning their DNA is constantly changing. This instability arises from defects in the systems that repair DNA damage, leading to an accumulation of genetic alterations. This high mutation rate acts as an engine for evolution, allowing cancer cells to rapidly generate the diversity needed to develop new traits and adapt to challenges like drug therapies.
Paradoxically, inflammation, a process associated with fighting infection and healing, can also contribute to cancer progression. While acute inflammation can help the immune system combat tumors, chronic inflammation has the opposite effect. An inflammatory environment can supply tumors with growth factors, enzymes that help with invasion, and signals that promote angiogenesis. This tumor-promoting inflammation can foster multiple hallmark capabilities.
Therapeutic Targeting of the Hallmarks
The framework of cancer hallmarks has provided a roadmap for the development of modern cancer therapies. By understanding the specific capabilities that cancer cells acquire, scientists can design treatments that target these mechanisms directly. This approach has led to more precise drugs that interfere with the processes tumors rely on to survive. This has shifted treatment strategies from broad-spectrum chemotherapies toward more targeted approaches.
Many successful cancer drugs are designed to inhibit a specific hallmark. For instance, immunotherapies known as immune checkpoint inhibitors target the “avoiding immune destruction” hallmark. These drugs block the signals that cancer cells use to deactivate T-cells, thereby unleashing the patient’s own immune system to attack the tumor. This approach has proven effective in treating a variety of cancers.
Other therapies are tailored to different hallmarks. Anti-angiogenic drugs, for example, target “inducing angiogenesis” by blocking the signals that tumors send to recruit new blood vessels, starving them of nutrients. For cancers with specific genetic vulnerabilities, such as those with mutations in BRCA genes, PARP inhibitors are used. These drugs target “genome instability” by blocking a DNA repair pathway, causing overwhelming DNA damage and cell death specifically in cancer cells.