Unlike the worthless, trillion dollar, forty year "war on drugs" (run by rightwing ideologues), the forty year "war on cancer" (run by scientists) has resulted in a deep understanding of cell biology. Parallel advances in genomics, metabolism, immunology, and protein structure are producing a synergistic explosion in our knowledge of how to detect and combat cancer.
This understanding includes, among other things:
- Identifying the normal cellular processes that cancer cells use at the wrong time, in the wrong places.
- Decoding the "circuit diagram of cell signaling"
- Understanding which aberrant signals lead to cancer
- Understanding the significance of the abnormal glucose metabolism of cancer cells
- Locating even small tumors by measuring that metabolism with PET scans
- Recognizing the involvement of immune system in protecting cancers
Oh, you haven't heard about any of this? Well, follow me below the fold to hear more.
It is symptomatic of our degraded media environment that a complex subject like the nature of cancer is superficially, if not misleadingly, reported. With their soundbite mentality, all the corporate media can do is mumble vaguely about miracle cures and "breakthroughs". (And, never, ever give the government credit for its massive funding of fundamental research in biology.)
Of course, any explanation of the failure modes (cancer) of an extremely complex system (our bodies) is, itself, going to be a very complex thing. That's why you won't find a quick overview, like the one I'm about to give, in the dumbed-down and sensationalized corporate media - including supposedly science-oriented popular magazines. Making people think about complicated things, just because they are important and fundamentally of interest in themselves, is the last thing the corporate media want to do. (Because people also might start making connections between the biology of cancer and the behavior of our financial institutions - which I will do in a subsequent essay.)
I have tried to organize this attempt at popularization in some kind of logical progression, but with all the feedback loops involved in cellular control and its disruptions, its inevitable that references to things that haven't yet been discussed will turn up. I beg your indulgence to continue to read past such problems. (And remember, Google and Wikipedia are your friends.)
1. When and where do cancer cells arise?
"Tumors are the wound that never heals". - Virchow.
Most people understand that cancer is a normal cell "program" gone wrong. But, since the underlying "program" of cell metabolism and inter-cellular signaling is so complicated, little insight is gained from this simple understanding. (For just some idea of signaling pathways, look at a diagram of any one of them. Then, just so you see that it is possible to disentangle this complexity, peruse the table of signals that cause various diseases.)
One way to begin to understand what signaling has gone wrong in cancer is to appreciate that, among other things, it hijacks the entire mechanism of "wound healing" to support its effort to grow unstoppably.
The response of the body to a cancer is not a unique mechanism but has many parallels with inflammation and wound healing...We suggest that the inflammatory cells and cytokines found in tumours are more likely to contribute to tumour growth, progression, and immunosuppression than they are to mount an effective host anti-tumour response...
Local inflammaton and systemic anti-inflammation: a paradox
In terms of inflammatory reactions, neoplastic disorders constitute a paradox. Tumours produce inflammatory cytokines and chemokines and are infiltrated by leucocytes. However, neoplastic disorders are associated with a defective capacity to mount inflammatory reactions at sites other than the tumour, and circulating monocytes from cancer patients are defective in their capacity to respond to chemo-attractants.
- You can read the rest of this excerpt's paper.
You can also read a briefer "news" article.
Another important topic in the origin of cancer is the still controversial topic of "cancer stem cells". To utterly oversimplify this topic, some people propose that cancer cells start from an ordinary stem cell (whose job is to reproduce indefinitely, when called upon, in order to replace damaged cells or to grow new tissue). Experiments have shown that (for some types of cancer) 99% of the cells of a tumor will not cause cancer when transplanted to a new host; but that cancer cells with "markers" identifying them as stem cells will cause cancer.
So, the cancer stem cell (CSC) proponents basically say that what has gone wrong is simple: a cell whose normal job is to proliferate has become un-regulated. This is not inconsistent with the wound healing theory because stem cells will go to the site of a wound.
You can read a 2001 review of CSCs
I would advise people new to the topic to avoid "controversies" like CSC. These are unsolved scientific problems, not scandals or misbehavior. The "controversy" will be settled by doing more and better experiments, not by politics.
2. Cancer onset is rarely a one-step process. A cancerous cell literally evolves.
Once a cell has turned cancerous (more on the details of that in item 3 below), a tumor grows until it outruns its local blood supply. Since its not supposed to be growing, the surrounding tissue does not create new blood vessels (a process called angiogenesis) to serve the tumor; and the tumor begins to become oxygen starved. Nature has evolved a large set of "subroutines" for dealing with low oxygen. This goes by the name of "the hypoxia response", and it involves turning on (and turning off) various metabolic systems.
Cancer cells literally evolve in the harsh, acidic, low oxygen micro-environment of the early, un-vascularized tumor. The stages of cancer correspond to mutations that either activate more oncogenes (genes that cause cancer) or deactivate more tumor suppressor genes.
You can read about how cancer cells evolve in a toxic micro-environment.
Wikipedia lists the stages of cancer:
• Stage 0 carcinoma in situ. (1)
• Stage I cancers are localized to one part of the body.
• Stage II cancers are locally advanced. (2)
• Stage III cancers are also locally advanced. (2)
• Stage IV cancers have often metastasized, or spread to
other organs or throughout the body.
(1) Carcinoma in situ (CIS) is an early form of carcinoma defined
by the absence of invasion of surrounding tissues. In other
words, the neoplastic cells proliferate in their normal habitat.
(2) Whether a cancer is designated as Stage II or Stage III can
depend on the specific type of cancer; for example, in
Hodgkin's Disease, Stage II indicates affected lymph nodes on
only one side of the diaphragm, whereas Stage III indicates
affected lymph nodes above and below the diaphragm. The
specific criteria for Stages II and III therefore differ
according to diagnosis.
A quick summary of the stages would be: Loss of control in situ; growth in situ; growth with vascularization; metastasis.
These days, because we realize that each cancer is genetically different, the DNA of individual tumors is analyzed to see exactly which mutations have occurred. The course of treatment for that individual patient depends on the genome of the cancer. There is even an international project to catalogue the most common cancer genomes: The Cancer Genome Project.
3. At the cellular level, what distinguishes a cancer cell from a normal cell?
Now that we have some idea of how cancers come about, we can start to dig into the massive understanding biologists now have of the intricate details of cellular metabolism - the tens of thousands of interacting proteins whose coordinated functioning maintains the equilibrium we call "life". People already know that a single broken protein can cause horrible diseases (e.g., cystic fibrosis, huntington's chorea) - that is, if it doesn't kill the developing fetus outright. We have just seen that a tumor progresses by collecting mutations suitable for a "career in cancer". This section will list what most scientists find to be the most important / distinguishing cellular behaviors in cancer.
The best paper on this topic is by Robert Weinberg, who won the Nobel Prize for his work on Cancer:
Six hallmarks of cancer (2000, Cell)
The hallmarks cited in this paper, which have become a standard in the field, are:
"Acquired capabilities of Cancer"
SIGNALING (i.e., de-regulation)
- Self-sufficiency in growth signals - bad signaling
- Insensitivity to anti-growth signals
- Evading apoptosis. Avoidance of immuno-surveillance
UNREGULATED GROWTH
- Limitless replicative potential
- Sustained angiogenesis
- Tissue invasion and metastasis
I'm not going to try to top a Nobelist in brief explanation. But, I will make some general points. Cancer cells basically "stop listening" to the signals that normally regulate them to grow only when it serves the body. It also suppresses internal signals to "commit suicide" due to massive DNA abnormalities. Finally, it manages to fool the immune system into thinking that its uncontrolled growth is "normal".
Isn't it just amazing how a cancer cell behaves exactly like a corporation whose management is into control-fraud? But, I digress.
4. In what ways are cancer cells' metabolism different? Why?
Within the last five years, a long-known fact about cancer has moved to center stage: the energy metabolism of a cancer cell is highly abnormal. If we all learned one thing in high-school biology, it was the "citric acid cycle" (a.k.a. the "Krebs cycle" or the "tricarboxylic acid (TCA) cycle"). We learned that this cycle increased the energy available versus anaerobic fermentation by a factor of 12. We learned that all multi-cellular creatures use the TCA cycle. Except, we have known for 50 years that cancer cells do not. Instead, they rely on anaerobic fermentation, even in the presence of massive amounts of oxygen. This strange metabolism is called the Warburg Effect, and it has been rigorously documented.
In fact, the presence of extremely high levels of fermentative by-products can be used by PET scans to detect even tiny clumps of cancer cells. Here is a series of FDG-PET scans following treatment with the "miracle" drug Gleevec.
The reasons for the Warburg effect are most interesting. It may get started in the early, low oxygen micro-environment of in situ tumors. Another (complicated) reason for the effect is that turning off the TCA cycle helps to prevent cell suicide (apoptosis). How? Well, it turns out that the TCA cycle takes place inside the mitochondria (the energy-producing organelle - i.e., sub-compartment of the cell); and that a broken mitochondria can send the signal to commit suicide. (See the mitochondria-apoptosis pathway. So, the takeaway is that: no TCA, no cell suicide.
After a tumor has vascularized, the Warburg metabolism actually becomes a way for the cancer cell to grow even faster. A normal, aerobic cell totally breaks down the incoming sugar into water, CO2, and energy. It then uses the energy to synthesize new proteins from basic metabolites. But, a cancer cell takes the tricarboxylic acids themselves as raw material, thereby lessening the amount of work it needs to do to produce new proteins.
Finally, it should be noted that the Warburg metabolism is very similar to the metabolism of primitive sweatshopping corporations - I mean primitive anaerobic bacteria.
5. Tumor-associated macrophages - the complicity of the immune system in cancer
By now, you may be noticing a slight agenda in my choice of topics. I assure you that, if you come to an understanding of the cellular biology of cancer, these associations will be quite obvious.
It is well accepted that cancer cells produce an inflammatory micro-environment. (This arises because of the anaerobic metabolism, which dumps large amounts of lactic acid out of the cell. But, beyond that, the cancer uses the toxic micro-environment to subvert the immune system.)
The presence of inflammatory cells in tumors was first described in 1863, and this has led to the concept that inflammatory microenvironment plays a key role to promote tumor development and progression. To read the excerpt below, you need to know that a macrophage is a cell that engulfs and destroys non-body/attacking cells. It is part of the immune system; and macrophages are found inside tumors.
The macrophages within the tumor, referred to as tumour-associated macrophages (TAMs), are the pivotal member of stromal cells. TAMs are derived from peripheral blood monocytes recruited into the tumor. Upon activation by cancer cells, the TAMs can release a vast diversity of growth factors, proteolytic enzymes, cytokines, and inflammatory mediators. Many of these factors are key agents in cancer metastasis. The presence of extensive TAM infiltration has been shown to correlate with cancer metastasis and poor prognosis in a variety of human carcinomas. TAMs promote cancer metastasis through several mechanisms including tumor angiogenesis, tumor growth, and tumor cell migration and invasion.
- Tumor-Associated Macrophage: Its Role in Cancer Invasion and Metastasis
One scientist argues that inflammation is the seventh hallmark of cancer.
6. Cachexia - when cancer steals so much energy that the rest of the body wastes away
Like a crooked bookkeeper, a tumor can steal small amounts without getting caught. But, as it grows it steals so much that the business (i.e., the host body) goes bankrupt (i.e., dies):
Because cancer cells ignore normal regulation, they suck up huge amounts of resources; and as the cancer grows, so does the resource usage. Since the cancer cell's demands for growth are not ignored, the rest of the body begins to starve - literally, to waste away. This phenomenon is called cachexia.
the selective expression of HK-2 by malignant tumors (is) part of a clever survival mechanism that allowed the tumor to continue metabolizing glucose regardless of the nutritional status of the tumor-bearing host. In fact, it could now be inferred why even at the terminal stages of cancer progression in a patient (i.e., tumor induced cachexia) the tumor will continue to scavenge glucose from the patient’s bloodstream and thrive while the patient’s physiology progressively shuts-down.
You can read the abstract of the article containing this excerpt.
7. SUMMARY
- Cancer starts when cells behave inappropriately - that is, they grow at the wrong time.
- Cancerous behaviors evolve in a progression, breaking free of regulation and commandeering resources.
- Cancer cell metabolism is highly inefficient, but it works - by stealing massive amounts of resources from the rest of the body.
- Parts of the immune (regulatory) system actually work to spread the cancer.
- Eventually, so much is stolen that the rest of the body collapses.
Anyone see any political analogies here?
LATE UPDATE: Thanks for putting this on the rec list! Its an honor to put something so technical on the list. And thanks to the posters for all the polite and well-informed comments and discussion.