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Old 12-01-2010, 12:14 PM
Dross Dross is offline
Join Date: Nov 2006
Posts: 883
Default Tumors bring their own support cells when forming metastases

The process of metastasis requires that cancer cells traveling from a primary tumor find a hospitable environment in which to implant themselves and grow. A new study from Massachusetts General Hospital (MGH) Cancer Center researchers finds that circulating tumor cells prepare this environment by bringing along from their original site noncancerous cells that support tumor growth. The report has been published online in PNAS Early Edition.

"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," says Dan Duda, PhD, DMD, of the Steele Laboratory for Tumor Biology in the MGH Department of Radiation Oncology, lead author of the report. "Our study shows that this primary soil also helps the initial growth of tumor seeds in a 'foreign' soil. This new role for these noncancerous cells is both a conceptual advance and offers potential new targets for treating or preventing metastatic disease."

Several previous studies by members of the MGH team and others have found clumps containing both tumor cells and stromal cells in blood and lymphatic vessels of cancer patients and have shown that these "passenger" stromal cells will proliferate along with the tumor cells if implanted at a new site. The current investigation was designed to determine whether primary tumors release fragments containing both tumor and stromal cells, whether those stromal cells survive and contribute to the development of metastases, and whether depletion of stromal cells could interfere with metastatic growth.

Several experiments in mice confirmed that implanted tumors shed both single tumor cells and clumps containing tumor and stromal cells and that tumor cells accompanied by stromal cells were more likely to survive. Not only did stromal cells from the original tumor proliferate at the site of metastasis, metastatic nodules that contained both tumor and stromal cells were more likely to survive and grow than were those containing tumor cells alone. Experiments using tumor cell lines known to be highly metastatic found that lung metastases that developed after a primary tumor was removed still contained stromal cells from the primary site and that reducing the number of stromal cells in lung metastases slowed tumor growth and increased the animals' survival.

To investigate whether stromal cells play a similar role in human metastatic tumors, the researchers examined brain tumor samples from patients with several different types of cancer for the presence of fibroblasts – stromal cells not normally present in brain tissue. Fibroblasts were frequently found in brain metastases – implying that stromal cells had traveled along with cancer cells from the primary tumor – but not in either primary brain tumors or normal brain tissue.

"We used fibroblasts in our experiments because they are frequently found in metastatic nodules, but we expect that other types of passenger cells – including immune cells and the endothelial cells that line blood vessels and other body cavities – also will play an important role in supporting metastasis," says co-corresponding author Dai Fukumura, MD, PhD, of the Steele Lab. "Cancer researchers here at the MGH and at other institutions are focused on detecting and analyzing circulating tumor cells, and our findings demonstrate that characterizing these non-cancerous passenger cells should also be a priority."

Adds Rakesh Jain, PhD, director of the Steele Lab and senior author of the PNAS Early Edition report, "Prevention of metastasis has been clinically difficult because these supportive nontumor cells arrive at the secondary site long before metastatic disease can be detected. Applying treatments that block participation of fibroblasts or other stromal cells in metastatic lesions at the time the primary tumor is removed could help prevent the spread of localized tumors."

Last edited by gdpawel : 09-21-2012 at 04:40 PM. Reason: post full article
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Old 12-01-2010, 10:04 PM
gdpawel gdpawel is offline
Join Date: Feb 2007
Location: Pennsylvania
Posts: 4,360
Default Trafficking of Cancer Cells

The trafficking of cancer cells to their final destination may be guided by factors produced by stromal cells of their host organ.

For example, Melanoma cells are closely related to CNS cells. Breast cancer cells more commonly are found in the posterior pituitary. Renal, gastrointestinal and pelvic are cancers tend to metastasize to the cerebellum.

All malignant cells that could evolve will use normal cellular machinery to engage in proliferation and invasiveness. The machinery can be in the malignant cell or its microenvironment, including stromal cells.

Genomic platforms have identified several prognostic and predictive factors, but the comparatively small number of known cellular analytes has limited their broad application.

To address the complexity and reduncancy of cell-death signaling pathways, clinical oncologists have applied the functional profiling platform to select therapies for chemo-naive patients with metastatic cancer.

The funcitonal platform uses morphologic and metabolic endpoints to gauge cellular response to drugs and signal transduction inhibitors in human tumor microspheroids isolated from surgical biopsies.

By examining drug-induced cell death events in native-state microspheroids, the funcitonal profiling platform has the unique capacity to capture stromal, vascular and inflammatory cell interactions with tumor cells, known to be crucial for clinical response prediction.

Citation: J Clin Oncol 27, 2009 (suppl; abstr e15124)

There was a symposium in Washington DC in September of 2009, devoted entirely to the circulating tumor cells (CTC) technology. Although it's a monitoring system to determine if therapy is working, it is not of value in selecting therapy (drug selection).

Circulating tumor cells (CTCs) are cancer cells that have detached from solid tumors and entered the blood stream. This can begin the process of metastasis. To metastasize, or spread cancer to other sites in the body, CTCs travel through the blood and can take root in another tissue or organ.

In stem cell research, anti-cancer treatments often effectively shrink the size of tumors, but some might have the opposite effect, actually expanding the small population of cancer stem cells that then are capable of metastasizing.

The technique requires only a simple blood draw from a patient, but its sensitivity and specificity allow physicians to observe true changes in CTCs that are greater than or less than the 5 CTC cutoff. This information may help physicians predict progression-free and overall survival in individual patients both before and following a single cycle of therapy.

The cutoff is 5 tumor cells. Less than 5 means that things are going well. More than 5 means that things are going poorly. But you can see the difference between 4 and 6 is not all that great. What they found out from that symposium was that it's perhaps useful as an adjunct to traditional methods for following tumor response, such as x-rays, blood tests, CTs, MRIs, history, physical exam, etc.

Basically, CTC labs use "negative selection" to isolate alleged circulating tumor cells. What that means is methods to "selectively" remove circulating normal cells, such as monocytes, lymphocytes, neutrophils, circulating endothelial cells, etc. The problem is that these normal cells outnumber circulating tumor cells by a factor of a million to one, and no "negative selection" procedure (or combination of procedures) can possibly strip away all the normal cells, leaving behind a relatively pure population of tumor cells.

What you have to do is to use a "positive selection" procedure, meaning selectively extracting the tumor cells out of the vastly larger milieu of normal cells. The problem is, when you do this, there is only a teeny tiny yield of tumor cells:

Here's from Wikipedia:

Circulating tumor cells are found in frequencies on the order of 1-10 CTC per mL of whole blood in patients with metastatic disease. For comparison, a mL of blood contains a few million white blood cells and a billion red blood cells.

So, from a typical 7 ml blood draw into a purple top tube, you are going to get, on average, 7 to 70 tumor cells -- total. This may be sufficient for certain molecular type tests (although the degree to which this tiny sample of cells is representative may be questioned), but it isn't nearly sufficient to test even a single drug in a cell culture assay, where one requires millions of cells for quality testing, including requirements for negative and positive controls.
Gregory D. Pawelski

Last edited by gdpawel : 09-21-2012 at 04:40 PM. Reason: additional info
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