Normalizing tumor vessels to improve cancer therapy

August 25, 2008,

Chemotherapy drugs often never reach the tumors they're intended to treat, and radiation therapy is not always effective, because the blood vessels feeding the tumors are abnormal—"leaky and twisty" in the words of the late Judah Folkman, MD, founder of the Vascular Biology program at Children's Hospital Boston.

Now, Vascular Biology researchers have discovered an explanation for these abnormalities that could, down the road, improve chemotherapy drug delivery. Their findings were published in the August 12 issue of the Proceedings of the National Academy of Sciences.

A tumor's capillaries—small blood vessels that directly deliver oxygen and nutrients to cancer cells—are irregularly shaped, being excessively thin in some areas and forming thick, snarly clumps in others. These malformations create a turbulent, uneven blood flow, so that too much blood goes to one region of the tumor, and too little to another. In addition, the capillary endothelial cells lining the inner surface of tumor capillaries, normally a smooth, tightly-packed sheet, have gaps between them, causing vessel leakiness.

"These abnormal features of tumor vessels impair delivery of circulating chemotherapeutic drugs to the actual tumor site" says Kaustabh Ghosh, PhD, first author on the paper, and a postdoctoral fellow in the laboratory of Donald Ingber, MD, PhD, the paper's senior author and interim co-director of the Vascular Biology program.

The idea of a therapy aimed at normalizing a tumor's blood vessels, to ensure that chemotherapeutic agents reach the tumor, has already been explored, but these attempts have only targeted soluble factors, particularly vascular endothelial growth factor (VEGF). Tumors secrete VEGF in abundance; it not only promotes blood vessel growth (angiogenesis), but makes them leaky. While blocking VEGF action helps reduce leakiness and improves vessel function, the effects have been transient, Ghosh says.

Ghosh and Ingber took a different approach, focusing on the role of mechanical forces on tumor blood vessels, which had previously been ignored. Past studies by Ingber and colleagues have shown that a capillary cell's sensitivity to soluble angiogenic factors like VEGF—and subsequent blood vessel formation—are determined by the mechanical balance between the cell's internal state of tension or contraction, and that of the surrounding support structure, or matrix, to which the cell adheres. These forces guide normal vascular pattern formation. Because tumor vessels are malformed, Ghosh wondered whether tumor capillary cells have lost the normal cells' ability to sense and respond to changes in matrix stiffness and distortion.

To address this question, the researchers studied capillary cells isolated from mice prostate tumors, provided by Andrew Dudley, PhD, in the lab of Michael Klagsbrun, PhD, in the Vascular Biology Program, and exposed them to cyclic mechanical stress—mimicking the pulsatile nature of blood flow and matrix distortion resulting from rhythmic heart beats. They found that normal capillary cells aligned themselves uniformly perpendicular to the force direction, but most of the tumor capillary cells failed to reorient, says Ghosh. These cells were "all over the place," and due to this lack of alignment, gaps appeared between neighboring cells, which may explain the increased vessel permeability.

Ghosh and colleagues also found that tumor capillary cells sense and respond to matrix rigidity differently than normal cells. When placed on a stiff surface, mimicking the tumor matrix, the cells tended to keep spreading even after normal capillary cells stopped doing so. Because of these differences in "mechanosensing," the tumor capillary cells were able to form capillaries even when cell densities were very low, while normal cells failed to do so. At higher cell densities, normal cells formed nice capillaries, whereas the tumor cells balled up into tangled clumps, creating the irregular patterns seen in many images of tumor blood vessels. "Because high cell density increases contractility across the entire cell layer, these findings suggested that tumor capillary cells are inherently hyper-contractile," says Ghosh.

The researchers went on to find that this hyper-contractility results from an increase in the levels of a protein called Rho-associated kinase (ROCK), which controls tension within the cell. When they treated tumor capillary cells with an inhibitor of ROCK, they normalized the behavior of the tumor capillary cells, so that the treated cells exhibited near-normal mechanical responses and formed more regularly-shaped tubular vessels.

Source: Children's Hospital Boston

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E_L_Earnhardt
not rated yet Aug 25, 2008
If ANGIOGENSIS PRECEEDS TUMOR FORMATION you are close to CAUSE AND CURE! See if AG can be caused
or accelerated by X-ray!
gdpawel
not rated yet Sep 17, 2008
In normal tissue, new blood vessels are formed during tissue growth and repair, and the development of the fetus during pregnancy. In cancerous tissue, tumors cannot grow or spread (metastasize) without the development of new blood vessels. Blood vessels supply tissues with oxygen and nutrients necessary for survival and growth.

Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels and have a remarkable ability to divide and migrate. The creation of new blood vessels occurs by a series of sequential steps. An endothelial cell forming the wall of an existing small blood vessel (capillary) becomes activated, secretes enzymes that degrade the extracellular matrix (the surrounding tissue), invades the matrix, and begins dividing. Eventually, strings of new endothelial cells organize into hollow tubes, creating new networks of blood vessels that make tissue growth and repair possible.

Most of the time endothelial cells lie dormant. But when needed, short bursts of blood vessel growth occur in localized parts of tissues. New capillary growth is tightly controlled by a finely tuned balance between factors that activate endothelial cell growth and those that inhibit it.

About 15 proteins are known to activate endothelial cell growth and movement. At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and basic fibroblast growth factor (bFGF), are expressed by many tumors and seem to be important in sustaining tumor growth.

Angiogenesis is also related to metastasis. It is generally true that tumors with higher densities of blood vessels are more likely to metastasize and are correlated with poorer clinical outcomes. Also, the shedding of cells from the primary tumor begins only after the tumor has a full network of blood vessels. In addition, both angiogenesis and metastasis require matrix metalloproteinases, enzymes that break down the surrounding tissue (the extracellular matrix), during blood vessel and tumor invasion.

Research has shown that controlling production of new blood vessels can restrict tumor growth, often prolonging the life of the cancer patient. Perhaps the most widely-used anti-angiogenic agent to emerge to date has been the drug Avastin.

It is increasingly being realized that circulating microvascular cells may be important markers for a wide variety of cancers. An article appeared in the September issue of Journal of Internal Medicine, "Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood," reported a novel system that was developed for testing anti-microvascular drug effects in fresh biopsy specimens of human tissue, cavitary fluids and blood.

Three-dimensional microclusters of tumor cells were isolated from fresh tumor biopsy specimens and cultured for 96 hours (polypropylene, round-bottomed, 96-well microplates) in the presence and absence of test drugs. A private laboratory has worked with the use of DMSO and/or alcohol as an anti-angiogenic enhancer and potentiator and has measured it with fresh "live" tumor specimens in cell culture assays.

What alcohol does is to reduce the secretion of VEGF by the tumor cells. The assay shows the abrogating effect of alcohol upon VEGF. It both reduces VEGF and makes a drug like Avastin work better, possibly overcoming tumor resistance to Avastin. Alcolol may have a membrane effect, basically puts the cell to sleep so that it doesn't think it requires a blood supply. In the presence of a drug like Avastin, you have a lethel 1-2 combination which knocks out the new vessels which are dependent on VEGF for survival.

Confirmatory activities are ongoing. The system is being offered currently to selected clients on a research basis and as an adjunct to a standard assay or a tyrosine kinase assay.

Source: J Intern Med 2008; 264: 275-287

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