A tumor is not a uniform mass of identical cells, but a complex collection of cells with different functions. Within this mix exists a small population known as cancer stem cells (CSCs). These cells possess properties similar to normal stem cells, most notably the ability to generate the variety of cells that constitute an entire tumor. A helpful analogy is to think of a tumor as a weed and the CSCs as its root; while you can cut the weed, it will grow back unless the root is removed.
The discovery of CSCs has shifted the understanding of how cancer develops and progresses. Their presence helps explain why some cancers are difficult to fully eradicate, leading to new research focused on targeting these specific cells to improve treatment.
Defining Characteristics of Cancer Stem Cells
The defining features of cancer stem cells are their dual capacities for self-renewal and differentiation. Self-renewal is the process by which a stem cell divides to form more stem cells, maintaining the core CSC population. This ensures the “root” of the tumor remains intact and capable of sustained growth.
Simultaneously, CSCs can differentiate, meaning they can also produce non-stem cancer cells, often called progenitor cells. These daughter cells then multiply to form the main mass of the tumor. This process creates the cellular diversity, or heterogeneity, observed within a single tumor.
In normal adult stem cells, this combination of self-renewal and differentiation is tightly regulated to repair and maintain tissues. In cancer, the signaling pathways that control these functions are dysregulated. This leads to uncontrolled self-renewal and abnormal differentiation that fuels tumor development.
Role in Tumor Progression and Metastasis
The biological properties of cancer stem cells directly drive the growth and spread of tumors. A single CSC may be sufficient to generate an entirely new tumor because its abilities allow it to establish a small population of stem cells while also producing the bulk tumor cells needed for expansion.
These cells are also central figures in metastasis, the process by which cancer spreads to distant parts of the body and the cause of over 90% of cancer-related deaths. It is hypothesized that CSCs are the cells capable of breaking away from the primary tumor, surviving travel through the bloodstream or lymphatic system, and seeding a new tumor in a distant organ.
To achieve this, CSCs can undergo a process known as the epithelial-mesenchymal transition (EMT), where they adopt characteristics that enhance their mobility and invasiveness. Once they reach a new site, they can revert to their original state to form a secondary tumor. CSCs can also promote the formation of new blood vessels, a process called angiogenesis, which supplies the tumor with nutrients and provides a route for metastasis.
Implications for Cancer Treatment
The existence of cancer stem cells affects how cancer is treated and why some therapies fail. Conventional treatments like chemotherapy and radiation are designed to be most effective against rapidly dividing cells. While these therapies can kill the bulk of cells in a tumor and cause significant shrinkage, they often fail to eliminate the CSC population.
One reason for this is that many cancer stem cells exist in a slow-dividing or dormant state known as quiescence. Because they are not actively proliferating, they can evade treatments that target the cellular machinery of rapid division. This allows a small number of CSCs to survive the initial therapy and later re-awaken to regenerate the tumor, leading to cancer relapse.
Cancer stem cells also possess inherent resistance mechanisms. They have highly efficient DNA repair systems that can fix the genetic damage caused by radiation and certain chemotherapy drugs. They are also equipped with molecular pumps, known as ABC transporters, that can actively eject therapeutic drugs from the cell’s interior. The survival of these resilient cells is a primary reason for treatment failure.
Therapeutic Strategies Targeting Stemness
In response to the challenges posed by cancer stem cells, researchers are developing therapeutic strategies aimed specifically at this population. These approaches focus on eliminating the cells responsible for regrowth and spread, with the goal of preventing relapse and improving long-term outcomes.
One approach involves targeting specific molecules, or markers, found on the surface of cancer stem cells. For example, proteins like CD44 and CD133 are often present on CSCs in various cancers. Therapies such as monoclonal antibodies can recognize these markers, bind to the CSCs, and trigger their destruction.
Another strategy focuses on disrupting the internal signaling pathways that CSCs rely on to maintain their “stemness,” such as the Notch, Wnt, and Hedgehog pathways. Drugs are being developed to block these specific pathways, cutting off the signals that tell a CSC to behave like a stem cell. This strips the CSCs of their ability to self-renew, depleting the reservoir of cells that fuel tumor growth.
A third strategy is to force the cancer stem cells to differentiate, an approach known as differentiation therapy. This method uses agents to push CSCs to mature into non-stem cancer cells. Once they become part of the bulk tumor population, they lose their self-renewal capabilities and become vulnerable to standard chemotherapy and radiation.