Cancer's Free Pass

Once a tumor is born, what is the likelihood that it will spread?  The ability of a tumor to metastasize, or spread, varies immensely.  

What is the magic free pass?

Tumors consist of cells sharing the aspect of unchecked growth, by which they are deemed cancerous. But they also differ in histologic or cellular type, and in aggressiveness, as well.  

Subpopulations of cells within tumors differ in multiple biologic aspects, including the tendency to migrate.   Those tumors containing higher proportions of cells prone to migrate successfully are those most likely to metastasize, almost in a Darwinian sense.   In fact, the extent of metastasis seems a better predictor of eventual outcome than other aspects, such as rapid growth, of the original tumor; dispersal is more deadly.  

Evidence exists that primary, or original, tumors may somehow keep their progeny in check. At times, after the primary tumor is removed, metastases seem to thrive, either because they are no longer inhibited by the primary tumor or because of lack of competition in that somewhat limited space, the body of the host.  

Although this issue is far from settled, it seems probable that primary tumor and metastases enjoy some form of connection.   Rapidly growing tumor cells may launch millions of cells into the circulation every day.  

Like fish fry, most of these fail to establish colonies; there are obstacles to be overcome.   The timetable of metastatic spread is but vaguely understood.  

Tendency of tumor cells to migrate is independent of tumor size; some tumors start to spread soon after the primary tumor becomes vascularized and some, such as breast carcinomas, when the primary tumor is less than 0.125 centimeters—The normal ability to see an object without magnified assistance is about 20 to 25 cm Thanks be to Wikipedia!

What happens to all these migrant cells, carried across the vast shores of the body by blood and lymph? Where do they tend to land?

Although in theory tumor cells could seed anywhere, in fact specific organs appear more likely to attract and nurture them.  In addition, certain kinds of cancer appear more likely to metastasize to particular places.

Is this travel and landing random? Probably not. (What is?)

A sequence of genes—a genetic signature—is starting to be recognized in solid tumors as predictive of spread long before any movement occurs.  Doctors at the Dana-Farber Cancer Institute and the Whitehead Institute reports that this tendency to metastasize can be detected as early as initial diagnosis.

Often, more deadly than the primary tumor is its progeny.
A separate question from spread is that of destination. Those that contain the genes for travel—Where do they tend to go?

The tendency of seeded metastatic cells to prefer certain destinations over others is known as tropism.   The first destination of blood flow from many organs is to capillaries in the lungs, which is a common site of spread. People have observed that breast cancers seem likely to spread to lymph nodes and lung tissue. The same is true for skin-cancer cells. Other common destinations are bone, liver, and brain.

It may be that cancer cells tend to get "stuck" in small capillaries anywhere, and there they settle. But other patterns of metastasis are not the simple outcome of blood flow, and the question is far from settled. Some organs may simply prove to be more, or less, fertile soils for planting.

In any case, as with spread, the answer to a cancer cell's destination is likely not random. Chemical signals like scents to a hound are probably involved, identically to what white blood cells do when they respond to injury.

Tropism is probably enabled by local growth factors or chemical factors called chemokines emanating like a trail of bread crumbs from the target organ.   Chemokine receptors that have indeed been found on specific cancer cells lead the cells along a chemokine-strewn path toward the organ that emits them. Researchers have shown that breast-cancer cells home in on chemokines from lymph nodes and lung tissue—favored sites of breast-cancer spread.

The series of events through which metastasis successfully occurs has been dubbed the metastatic cascade.  The process comprises a series of linked steps that must be accomplished by migrating cells for metastasis to occur.  Each step involves both cancer and host, and failure of any event to occur theoretically will interrupt the process.   Generally, the steps consist of tumor initiation and progression, migration, and colonization.    Within each step are subdivisions.

Initiation:  A tumor is born when an activated oncogene is triggered by some event that brings potential to fruition; suddenly control mechanisms are ineffectual, and cancer begins.   The cell that began the process replicates explosively while influencing neighboring cells.   DNA within the oncogenes may be selectively synthesized to produce more aberrant cells.   This process must be fed, and the tumor coaxes its host to provide the tumor with blood.   If the host obliges, the process continues.

Migration:  Tumors are encased in capsules called basement membranes.   If tumor cells are to spread, they must first it must b escape the capsule.   For a cell to escape, the capsule must be locally degraded.   Tumor cells secrete enzymes, or induce the host to provide enzymes, to degrade the capsule.   Invasion is a three-step process.   First, tumor cells attach to the capsule that contains them.   After attachment, the tumor cell either secretes degradative enzymes, or induces the host to do so, to degrade the matrix locally.   (In contrast, when normal cells or benign tumor cells attach to the matrix, they shift into a resting state.)  Finally, the tumor cell moves through the damaged capsule into the interstitial stroma between cells.   These cells move by means of self-induced motility factors much in the way an amoeba propels itself, and by chemical attraction.   The direction of locomotion may be driven by chemical cues (chemotaxis) or may be more random (chemokinetic); these chemical cues may be secreted by host or tumor cell.   Tumor cells may produce factors that increase their own ability to move about.  

Colonization:  Most tumor cells exit blood vessels through capillaries.   With surface-matrix receptors, single cells adhere to the inside luminal surface of capillaries, prompting protective epithelial cells to retract.   Retraction exposes the basement membrane.   Using enzymes, the tumor cell degrades the basement membrane.   As the membrane dissolves, the tumor cell extends a "false foot" or pseudopodia before it and exits through the zone of lysis (destruction).   Escaped cells then begin to collect in a germinal colony.   If they are to exceed a diameter of about 0.5 mm, newly established colonies require a new vascular supply.   When for various reasons one is not supplied, a tumor colony may remain dormant.   Other potential causes of dormancy are immunologic restraint, in which the tumor maintains "zero population growth" and dependency of tumor cells on growth factors provided, or not provided, by the host.   Thus, active or passive host defenses may stop or slow tumor progression at any step of metastasis.

Theoretically, blockage of any of the metastatic steps will arrest the spread of the cancer.   Antigens specific to tumors have been identified in animals.  But tumor-specific antigens have not yet been established in humans, and adjuvant immunotherapy thus far has had variable success.  Blocking angiogenesis and preventing proteolysis are likely candidates for pharmacologic strategies.  If the spread can be prevented, it may not even be necessary to kill tumor cells at primary and metastatic sites.  

Some people with cancer experience substantial weight loss—Weight loss that may surpass 10 percent of their body weight.  The condition is known as cachexia.

One defender.

 The Clock is Ticking           

 even in Boulder!