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June 16, 2006

New Stem-cell Findings Can Help The Body To Cure Itself

Topics: Medicine

boc0970185f01.gifYears ago in my early days of research at the university level, I found that by reading a broad range of literature from different disciplines, I was able to not only develop a better understanding of various mechanisms studied within the various fields, such as neurobiology, immunology, cell and molecular biology, genetics, oncology, and transplant medicine, I was more importantly, to me at least, able to better recognize patterns that could be utilized for drug development. Although my primary interest was immunopharmacology, the hard work and talents of all those basic research scientists could more quickly and more effectively benefit real patients if their collective results were applied synergistically.

I mention this here because researchers at Karolinska Institute have identified an important mechanism that regulates how many new cells are produced by each intestinal stem cell. The study is published in the latest issue of the prestigious scientific journal, Cell, and says that "This might eventually help us develop new drugs for things like neurological disorders and anaemia." They are right, however, the prospects for future development of pharmaceuticals from a better understanding of the mechanism that regulates how many new cells are produced by each intestinal stem cell, extend far beyond the field of neuroendocrinology and hematology - for example, cancer. Interestingly, this fact hasn't escaped the researchers at Karlinska (I've been there a few times - they're good people!):

In most organs of the body, old cells are continually being replaced by new. If too many new cells are produced, however, it can lead to overgrowth and tumour formation. Too few cells, on the other hand, can result in organ degeneration. It is therefore crucial that exactly the right number of cells are produced.

As many serious disorders cause a reduction in the production of new cells, scientists are keen to develop drugs that stimulate the process, which in turn could help the body to cure itself.

It has long been known that the new cells are often formed by immature cells known as stem cells, but the mechanism regulating the number of new cells produced has remained something of a mystery. However, in a new study to be published by Cell stem-cell researcher Jonas Frisén has succeeded in showing how the body's own stem cells do just this. Working alongside an American group of researchers, Professor Frisén and his team have identified a signal transduction process that regulates the degree of stem-cell division.

"Understanding how cell production is regulated increases our chances of producing drugs able to stimulate the endogenous production of new cells," says Professor Frisén.

He hopes that the new findings can be used to develop drugs that stimulate, for example, the formation of new nerve cells to treat conditions such as stroke and Parkinson's and skin cells to facilitate the healing of wounds.

"We also know that blood, brain and skin stem cells express the genes that we now know to be important in the intestine," he says. "This suggests that the cell production mechanism can be the same for these stem cells too."

The next step for Professor Frisén and his group is therefore to study how blood and skin stem cells go about producing new cells.

Read the entire article...

Here's a brief summary of some of the evidence for tumor initiating stem cells among tumors arising from a variety of tissues:

Currently, tumor stem cells have been isolated and characterized in several hematologic malignancies and two solid tumors. The critical experimental design that underlies all these studies is the development and use of a functional assay for tumor establishment and the prospective isolation of the T-IC. Often normal tissue stem cell markers are used to identify these populations, but a functional assay such as transplantation of human leukemic stem cells into immunodeficient murine models such as the NOD/SCID mouse is most important in identifying tumor initiating cells. One of the first tumors in which a stem cell was identified was acute myeloid leukemia (AML). In this disease, the frequency of the leukemic stem cell (LSC) was approximately 1 per million AML blasts, establishing that not every AML cell had LSC capacity. A CD34+, CD38- cell fraction representing 0.1-1% of the tumor cells possessed all the leukemia initiating activity in the NOD/SCID model. By contrast, the CD34+, CD38+ cells and the CD34- cells, which comprise most of the cells in the tumor, could not initiate leukemia. A multiple myeloma stem cell has also been characterized. Multiple myeloma cell lines and primary patient derived cells express the cell surface marker syndecan -1 (CD138). Expression appears during the course of B-cell differentiation. A population of cells representing <5% of the cells in the bulk population of multiple myeloma cells were found to be CD138- and possessed in vitro clonogenic potential. These cells also engrafted successfully into NOD/SCID mice, whereas CD138+ cells did not engraft. CD138- cells were also CD19+ and CD20+, and they expressed higher levels of KI67 (a cell proliferation antigen) than CD138+ cells. Recently a mammary carcinoma stem cell has been isolated primarily using three cell surface markers (CD44, CD24, and epithelial specific antigen). The tumor initiating capacity of the cells was verified in a NOD/SCID engraftment assay, and the T-ICs represented only 2% of the unfractionated cells.

Finally, a putative brain tumor stem cell has also been isolated. These cells appear to be between 0.3 - 25 % of the cells in the brain tumors examined. They are positive for the neural stem cell marker CD133 and have a marked capacity for self renewal and differentiation. Transplantation of these putative neural tumor stem cells into the forebrains of NOD/SCID mice yields tumors phenotypically resembling the tumors from which the stem cells were isolated.

All of this evidence has come from the hard work of basic researchers at research centers around the world. I'm often amazed at how little credit and appreciation is given to men and women who's work is responsible for understanding mechanisms so important to drug development. I'm also amazed at the progress that's been made in cancer treatment.

Study Says Stem Cell 'Fusion' Occurs In Tumors - Although the tumor in this study did not "initiate" tumors or become malignant, the researcher believes the fusion process is one explanation for how tumors acquire genetic instability and have the potential to give rise to malignant cancer. ... One promising result could be in better understanding the careful balance between rapid and effective regeneration after tissue injury, and minimizing the risk of cancer.

Mechanisms of Disease: from stem cells to colorectal cancer - Although the intestinal stem cell remains difficult to isolate, it is known to be important for the development of intestinal neoplasms.

Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer - ".. wt-APC, by progressively decreasing survivin and increasing apoptosis from crypt bottom to top, may limit the population size of stem cells and other proliferative cells in the lower crypt; mutant APC may allow expansion of these populations, thereby initiating tumorigenesis."

Posted by Richard at June 16, 2006 1:37 PM

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