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Colon Cancer’s Potential for Metastasis Determined Early
By Dross at 2008-03-07 00:00
Colon Cancer’s Potential for Metastasis Determined Early

Some colon cancers are destined to spread to the liver and other parts of the body, whereas others are successfully treated by surgical removal of the tumor. Now, Howard Hughes Medical Institute investigators have found that the ability of a colon tumor to metastasize arises early in its development.

Those colon cancers that spread carry the ability to metastasize from the time they become cancerous, the researchers found. They don't need to acquire any new genetic mutations to become metastaticterm. The research also suggests that once a colon carcinomaterm develops, if it is going to spread outside the colon, it will do so in less than two years.

“Our research implies that the genetic machinery that causes metastases is hard-wired into the tumor from the beginning.”
Sanford Markowitz

“The ability to metastasize is hard-wired into this group of tumors in the colon,” said Sanford Markowitz, a Howard Hughes Medical Institute investigator at Case Western Reserve University. “It isn't something that happens after a cancer cell wanders off and leaves the colon.”

Markowitz and his colleagues published their findings in the Proceedings of the National Academy of Sciences on March 3, 2008.

Colon cancer is the second leading cause of cancer mortality in the United States, causing about 60,000 deaths annually. But there are many more cases of colon cancer that are cured by surgical removal of the tumor. Markowitz and his team wanted to understand the genetic differences between the two types.

“It's clear that colon cancer comes in two very different varieties,” said Markowitz, who led the study. “With one variety, the surgeon cuts it out and the individual is cured. With the other variety, the surgeon cuts it out but the disease still spreads, and despite our best efforts the individual succumbs to the disease. So you have two hugely different biological behaviors that are literally the difference between life and death. And we wanted to know if we could find a genetic basis for that difference.”

To do so, the team compared the DNA of primary colon tumors to the DNA of tumors in the liver that had spread from the colon - the metastases. Markowitz said he was shocked to discover that, in 7 of 10 patients, there were no new mutations in the liver tumors. That means the ability of those tumors to spread from the colon was hard-wired from their inception.

In the tumors from the other three patients, a few new genetic mutations appeared in the liver metastases. But none of the mutations appeared in more than one patient. “My guess is that these mutations are noise, that they aren't responsible for the metastases,” said Markowitz.

1 comment | 2247 reads

by gdpawel on Tue, 2013-01-15 01:22
If detected early, most cancers seem to be curable. But the tumor's deadly offspring could be sleeping in the body.

Cancer dormancy is controlled by the tumor suppressor gene VHL (mutation associated with hyper-vascularity). Inactivation or silencing of VHL would cause single metastatic cells and micro-metastases to escape dormancy, pushing them to proliferate, expand, and invade the homing normal tissue.

Understanding the pathogenesis of disease has enabled researchers to develop new classes of drugs that target VEGF, both at the protein level (Avastin, Zaltrap) and at the tyrosine kinase level (Iressa, Nexavar, Sutent, Tarceva). An additional class of drugs targets the intracellular metabolic pathway known as mTOR (Afinitor, Torisel).

Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor genes don't work properly, cells can grow out of control, which can lead to cancer.

An important difference between tumor suppressor genes and oncogenes is that oncogenes result from the activation (turning on) of proto-oncogenes, but tumor suppressor genes cause cancer when they are inactivated (turned off).

Researchers talk about targeting the microenvironment (soil) may effectively kill cancer cells (seeds) through a small-molecular weight sequential dual-targeting theragnostic strategy, or dual-targeting approach.

The process of metastasis requires that cancer cells traveling from primary tumor find a hospitable environment in which to implant themselves and grow. Researchers found that circulating tumor cells prepare this environment by bringing along from their original site noncancerous cells that support tumor growth.

It has been known for some time that noncancerous stromal cells, which provide a support structure for tissues and organs, contribute to the growth of primary tumors, providing the "soil" in which tumors can grow. A study showed that this primary "soil" also helps the initial growth of tumor "seeds" in a foreign soil.

This role for these noncancerous cells is both a conceptual advance and offers potential new targets for treating or preventing metastatic disease. To this end, most investigators believe that treatment advances lie in the development of novel interventions that attack not only the "seed" but also the complicated stromal "soil" of this disease.

In regards to drug selection, that's why the functional cytometric profiling platform works so very well in this environment. It doesn't dismiss genetic testing, it uses all the information, measuring the interaction of the entire genome, to design the best treatment for each individual, not some average population.

It doesn't look at trial-and-error clinical literature search (population studies) to try and match therapies to patient-specific biomarker information to generate a treatment approach. It "actually" measures cancer drugs against your actual cancer cells. It's not theoretical but real-time analysis.

Regardless of all of this, most of the cells that leave home don't survive the journey in the blood or lymph systems and many cancerous cells that eventually do lodge in a distant organ simply remain dormant, leaving it up to the immune system to take care of them.

Full-blown metastasis is an extremely challenging trade and the great majority of cancer cells are not up to the task. Even those malignant characters that manage to slither their way into the blood or lymph system, usually fail to do anything further.

Most tumor cells lack the streamlined form of the blood and immune cells that are designed for cross-body trafficking, shear forces in the smaller vessels may rip the intruders apart. These free-floating cancer cells can remain in isolation from a tumor for over twenty years.

AACR Centennial Series: The Biology of Cancer Metastasis: Historical Perspective


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