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Signaling that promotes cancer metastasis

For over 2 decades it has been known that the fetus uses chemical signals to help direct the location of various structures such as nerves and blood vessels,  The mechanism as to why a particular type of cancer cell will almost always migrate to certain tissues (such as lung cancer to the brain, and prostate to the bones) was thought to have to do with the immune system and the markers on the cancer cells not appearing as foreign to the white blood sells of such as cancerous cells in the brain.  For over 15 years this process has been investigated:  how for example TGF receptors promote migration of the cancerous cells to certain target tissues.  (See for example Proc Natl Acad Sci U S A. 1994 September 13; 91(19): 8772–8776)


The article was published in the April 4 issue of Cell.


Researchers Learn How Signaling Molecule Orchestrates Breast Cancer's Spread



Researchers Learn How Signaling Molecule Orchestrates Breast Cancer's Spread
April 3, 2008

NEW YORK, NY - A study led by researchers at Memorial Sloan-Kettering Cancer Center has uncovered how breast tumors use a particular type of molecule to promote metastasis - the spread of cancer cells. Metastasis is the cause of approximately 90 percent of all cancer-related deaths. The study is published in the April 4, 2008, issue of Cell.

“Our work reveals how tumor cells learn to exploit cytokines...to promote the spread of breast cancer.”
-- Joan Massagué, PhD, study's senior author and Chairman of the Cancer Biology and Genetics Program at MSKCC and a Howard Hughes Medical Institute investigator

The work examines how cells in the body communicate with each other through cytokines, signaling molecules that direct a wide range of activities such as cell growth and movement. One important cytokine - transforming growth factor  (TGF) - normally suppresses tumor development. However, according to the findings, cancer cells in humans are able to misuse these cytokines for their own gain by compelling TGF to enhance a tumor's ability to spread instead of suppressing it.

Using computer-based analysis to classify patient tumor samples based on their levels of TGF, the researchers observed that about half of all breast tumors contained active TGF. The affected tumors were found to be more aggressive and more likely to metastasize to the lung during the course of the patients' disease.

Using mice for their next set of experiments, the researchers discovered that TGF prompts breast cancer cells to make a second cytokine, known as angiopoietin-like 4 (ANGPTL4), which enhances the ability of the cancer to spread to the lungs through the blood circulation. The results show that the breast cancer cells use ANGPTL4 to break down the thin capillaries of the lung, thus facilitating their escape into the lung tissue.

"Our work shows that TGF enhances human breast cancer metastasis and reveals how tumor cells learn to exploit cytokines by making them work as a relay system to promote the spread of breast cancer," said the study's senior author, Joan Massagué, PhD, Chairman of the Cancer Biology and Genetics Program at MSKCC and a Howard Hughes Medical Institute investigator.

The researchers are now seeking to determine whether TGF and ANGPTL4 may also be active in other types of tumors, and are evaluating ways to interfere with the action of these cytokines to prevent metastasis in cancer patients.

"Deciphering how cancer cells take advantage of these cytokines is essential for developing therapies that can prevent this process," said the study's lead author David Padua, a graduate student in Dr. Massagué's lab. "Because cytokines act outside of cells they can be more easily targeted by drugs that block their activity."

The study provides support for developing agents to interfere with TGFin order to prevent and treat cancer metastasis. It points at ANGPTL4 as a possible target to interrupt the TGFstimulus of metastasis without interfering with the molecule's beneficial effects. Several pharmaceutical companies are currently testing TGF-blocking compounds in clinical trials as candidate drugs against breast cancer, melanoma, and other types of cancer.

This work was co-authored by Xiang H-F. Zhang and Qiongqing Wang of MSKCC's Cancer Biology and Genetics Program, and William L. Gerald, MD, PhD, a surgical pathologist and member of the Human Oncology and Pathogenesis Program at MSKCC. Cristina Nadal, PhD, of the Hospital Clínic-IDIBAPS and Roger R. Gomis, PhD, of the Institute for Research in Biomedicine (IRB Barcelona), both of Barcelona, Spain, also contributed to this research.

The study was funded by grants from the National Institutes of Health, the Kleberg Foundation, the Hearst Foundation, and the BBVA Foundation.



More on their research” 

The TGF-beta signature was responsible for this selectivity, they identified a second element in the relay, a signaling molecule called angiopoietin-like 4 (ANGPTL4), whose expression is induced by TGF-beta. ANGPTL4 disrupts capillary walls, loosening the connections between adjacent cells and allowing the metastasizing cells to "seed" the tissue. Disrupt TGF-beta signaling, or ANGPTL4 expression, and lung metastasis is disrupted, the researchers found. Enhance that signaling, and lung metastasis is increased.  Massague said the reason ANGPTL4 helps cells colonize the lungs but not the bone has to do with the different architecture of the two tissues. Lung tissue is highly vascularized, yet capillaries present a relatively impenetrable barrier to metastasizing cells. Bone, on the other hand, is different, Massague explained, because it has windows and "...every day in the bone marrow, the capillaries have to let cells in and out.  It's likely to be a combination of genes, and this particular one [ANGPTL4] is one of them.” 

Joan Massague is chairman of the Cancer Biology and Genetics Program. 


Neoplasia. 2003 May; 5(3): 267–277

The Loss of TGF-β Signaling Promotes Prostate Cancer Metastasis1



In breast and colon cancers, transforming growth factor (TGF)-β signaling initially has an antineoplastic effect, inhibiting tumor growth, but eventually exerts a proneoplastic effect, increasing motility and cancer spread. In prostate cancer, studies using human samples have correlated the loss of the TGF-β type II receptor (TβRII) with higher tumor grade. To determine the effect of an inhibited TGF-β pathway on prostate cancer, we bred transgenic mice expressing the tumorigenic SV40 large T antigen in the prostate with transgenic mice expressing a dominant negative TβRII mutant (DNIIR) in the prostate. Transgene( s) and TGF-β1 expression were identified in the prostate and decreased protein levels of plasminogen activator inhibitor type I, as a marker for TGF-β signaling, correlated with expression of the DNIIR. Although the sizes of the neoplastic prostates were not enlarged, increased amounts of metastasis were observed in mice expressing both transgenes compared to age-matched control mice expressing only the large T antigen transgene. Our study demonstrates for the first time that a disruption of TGF-β signaling in prostate cancer plays a causal role in promoting tumor metastasis.



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