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I admit this post is a little long, but this is a fantastic starting point to understand the biology of cancer. I am going to summarize one of the most influential academic articles on cancer ever written: “The Hallmarks of Cancer” by Douglas Hanahan and Robert Weinberg (freely available here )
The paper presents no original experiments, rather it is a review article; a summary of decades of research, organized and categorized into separate hallmarks of the disease. The authors are both highly respected cancer biologists who have both spent decades studying the disease. Although Hanahan and Weinberg’s opinions carry much influence on their own, they back up their conclusions with no shortage of references to peer-reviewed research.
Although this article was originally published on January 7th 2000 (eons ago in scientific terms) the concepts are nonetheless a very good starting point for understanding the basic biology of cancer. Indeed, every time an undergraduate or intern begins doing research in our lab, I make sure they have read and understand the paper.
Ok, let’s begin…
The trek of a “normal” cell becoming a cancer cell is a long one, and changes are physically manifested in alterations of the cell’s DNA, known as mutations. A cancer cell must acquire many mutations to begin damaging tissues and causing problems. For many cancers this process can take decades.
Hanahan and Weinberg categorize cancer as having six traits:
1) Self-sufficiency in growth signals
Cellular division and growth are extraordinarily regulated events in multicellular organisms (like us). With hundreds of different types of cells, organized in critical architectural patterns, the homeostasis (internal equilibrium) of an organism demands exquisite coordination. The growth (and migration, which I’ll get to) of cells is regulated in many, many different ways. However, most cells require chemical cues known as “growth factors” in order to begin cell division. Cancer cells must divide in order to establish tumors, along with growth signals. Often, local chemical cues help cancer cells divide, or the cancer cells secrete their own growth factors. Or, sometimes cancer cells develop mutations that allow growth without growth factors.
2) Insensitivity to anti-growth signals
With Yin there must be Yang, and in most adult tissues there are many anti-growth signals present. Cancer cells must be able to become insensitive to cues from the surrounding tissues that keep most cells from dividing.
3) Evading apoptosis
Apop… what? Apoptosis (A-pop-tO-sis) is programmed cell death. Our tissues are in a constant balance (dynamic equilibrium) of cell death and renewal. Every day, 50-70 billion cells in our body purposefully die and new cells grows into their place. This turning over of cells is how the body keeps tissues young and fresh.
Apoptosis is an orchestra of entropic deconstruction. Instead of a cell simply bursting its membranes and spewing out all its contents and damaging nearby tissues, apoptosis involves the orderly partitioning of cellular components into self-contained units that are easily cleared by the immune system or eaten up by nearby cells. In that capacity, apoptosis is akin to recycling, as the biochemical building blocks are re-used to create a new cell.
Apoptosis is also the body’s natural defense mechanism against cancer development. Often, cells that become damaged (radiation, trauma, oxidative damage, etc.) will initiate apoptosis preemptively because those type of cells will often harbor DNA mutations that could give rise to cancer. Given how often mutations can occur in healthy tissues, and the dynamic equilibrium of death and renewal amid tight tissue architecture, it is amazing that we do not get cancer more often.
Cancer cells must develop ways to resist internal and external signals to self-destruct. Often cancer cells will lack or have mutated versions of genes essential for apoptosis.
4) Limitless replicative potential
All somatic (non-reproductive organ) cells in the body have yet another defense mechanism against cancer: a finite number of cell divisions possible before the cell undergoes apoptosis, or simply remains in a limbo-like indolent state. If I were to take a skin biopsy from your arm, I could take those cells and grow them in a special petri dish for several weeks before the cells would simply stop growing.
At the end of chromosomes there are structures called telomeres that act as caps to the reactive DNA ends. Each time a cell divides, the cap gets smaller and smaller, until eventually it cannot divide any more. Cancer cells often find ways around this, usually by turning on telomerase, a special gene that is only turned on in reproductive organs. There are cancer cell lines in use today in laboratories around the world that are 50+ years old; the original donor having died many years ago. Given correct growing conditions, cancer cells are effectively immortal.
5) Sustained angiogenesis
Angiogenesis is a name given to the process of new blood vessel growth. Any tumor beyond 1mm in size must acquire an oxygen supply. Growing tumors recruit blood vessels from surrounding tissues and effectively tap into the body’s oxygen and nutrient supplies. Often, the interlacing blood vessels can make surgery difficult. However, since adults generally go not have any new blood vessel growth (minus menstruation and traumatic wound healing) the biochemical patterns present on these new blood vessels in cancer patients can be targeted by advanced therapeutics to literally starve off nutrients to tumors.
6) Tissue invasion and metastasis
The late Judah Folkmann once said that patients do not die from cancer. They die from cancer metastasis. Of all the aforementioned hallmarks of cancer, it is only when cancer spreads and begins to disrupt the architecture and homeostasis of to vital organs that it becomes a deadly disease. For many patients, the primary tumor is operable and can be readily removed. It can take decades for a tumor to acquire the mutations that enable it to spread to new tissues, but tumors can grow for decades in the body without the patient noticing. Symptoms are often similar to the common cold or flu, or not present at all. This is why most patients that present with cancer in the clinic already have advanced stage cancer. This is also why detection of cancer in its early stages is paramount to its treatment.
In addition to these concepts, one can think of cancer as a microcosm of natural selection and evolution. The trek from a “normal” cell to a cancer cell is a long one, and requires sequential mutations over time that manifest these adaptations, or “hallmarks.” They might come in one form or another, but the one thing to understand about the order is that generally metastasis comes last, and that it is the most pathological aspect of cancer. If we are to truly combat cancer, we need mechanisms to detect cancer in its earlier stages, as well as effective means to target cancer that has already begun to spread.
If you have read this far, thank you! Feel free to email me with questions.