Blood vessel cells coax colorectal cancer cells into more dangerous state
Blood vessels that supply oxygen and nutrients to tumors can also deliver something else - a signal that strengthens nearby cancer cells, making them more resistant to chemotherapy, more likely to spread to other organs and more lethal, scientists at The University of Texas MD Anderson Cancer Center report online in Cancer Cell.
Working in human colorectal cancer cell lines and tumor samples, as well as mouse models, the researchers found that endothelial cells, which line the inside of blood vessels, can trigger changes in cancer cells without even coming into direct contact with them.
This signaling by the endothelial cells causes colorectal cancer cells to take on the attributes of cancer stem cells, said Lee M. Ellis, M.D., professor in MD Anderson's Departments of Surgical Oncology and Cancer Biology and senior author of the paper.
"Cancer stem cells initiate and sustain tumor growth, promote metastasis and resistance to chemotherapy and have a variety of other attributes," Ellis said. "We've identified a new way that elements of a tumor's microenvironment, in this case endothelial cells, promote the conversion of malignant cells into cancer stem cells."
The team found the blood vessel cells use a previously unknown method of activating the Notch molecular pathway in colorectal cancer cells to initiate that conversion.
Possibilities for Notch-inhibiting drugs
Notch is a receptor protein found on a cell's surface that had been thought to be activated only by ligand proteins on the surface of other cells. Cell-to-cell contact was required. Notch is important to many cellular functions, including formation of new blood vessels, but it is often haywire in cancers.
"Our findings imply that Notch inhibitors under development and now in clinical trials might be able to affect tumor cells directly, through their vasculature, or both" Ellis said.
Colorectal cancer is the second-leading cause of cancer death in the United States, with 50,000 deaths caused annually by untreatable metastatic disease. A tumor's microenvironment, which includes blood vessels, supportive tissue and conditions such as hypoxia - lack of oxygen - is the soil that nurtures the metastatic tumor seed.
Jia Lu, MS, first author on the paper, and colleagues focused on the possible impact of endothelial cells on cancer stem cell promotion. In a series of experiments performed by a team of investigators at MD Anderson and other institutes, the researchers systematically laid out the connection between endothelial cells and colorectal cancer stem cells.
- Culturing human colorectal cancer cells with endothelial cells increased the number of cancer cells that express two markers of cancer stem cells, CD133 and ALDH activity.
- Growing cancer cells in endothelial cell-conditioned medium increased the CD133 positive cells by seven-fold, the ALDH-positive cells by 16-fold and caused a six-fold increase in sphere-forming capability, another hallmark of cancer stem cells.
- In a mouse model experiment, colorectal cells in medium conditioned with endothelial cells led to increased tumor formation and faster growth than did cells grown in a control medium,
- Endothelial cell conditioned medium treated colorectal cancer cells formed more metastases than colorectal cancer cells treated with control conditioned medium. In one study of liver metastasis, 9 of 10 mice injected with treated cancer cells grew liver metastases, compared to only 3 of 10 in the control group.
- Colorectal cancer cells cultivated in endothelial cell-conditioned medium survived longer when treated with two types of chemotherapy.
- Analyzing the presence of molecular networks known to be involved in cancer stem cell development, only the Notch pathway was activated in treated colorectal cancer cells.
- Notch is activated in colorectal cancer cells adjacent to endothelial cells in human tumors.
- Having previously found that endothelial cells secrete soluble proteins, the team found a soluble form of Jagged-1 activated Notch to promote cancer stem cell conversion. Jagged-1 was previously known only as a Notch-activating ligand anchored on the surface of another cell.
- They then established that the protease ADAM17 cleaves a part of Jagged-1 off to produce its soluble form.
- Cell line and mouse experiments showed that blocking production of ADAM17 with small interfering RNA or with an inhibitor of the protease blocked the formation of colorectal cancer stem cells.
The mode of cell signaling involved in this chain of events is paracrine signaling - interaction among two different types of cells via soluble mediators rather than direct contact. However, recently Shahin Rafii, M.D., from Weill Cornell Medical College termed signaling between endothelial cells and other target cells "angiocrine signaling," terminology that Ellis supports.
Six drugs are approved for treatment of metastatic colon cancer, including ones that target blood vessels that support tumors. But there has been no dramatic improvement for patients, with median overall survival still less than two years.
With much additional research, the team's findings could lead to more refined targeted therapies for metastatic colorectal cancer.
Future studies will focus on other factors secreted by endothelial cells that promote cancer cell aggression. "It's clear that endothelial cells are more than just a conduit for blood delivery. In fact, in preliminary experiments, it appears that endothelial cells secrete more proteins than do cancer cells. This work, of course, requires validation".
Journal reference: Cancer Cell
Provided by University of Texas M. D. Anderson Cancer Center
- Potential new colorectal cancer treatment target identified Oct 07, 2012 | not rated yet | 0
- New role for Vascular Endothelial Growth Factor in regulating skin cancer stem cells Oct 19, 2011 | not rated yet | 0
- How tumor cells create their own pathways Jul 10, 2012 | not rated yet | 0
- Stemming the spread of cancer Sep 21, 2012 | not rated yet | 0
- Therapy may block expansion of breast cancer cells Nov 05, 2008 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
Researchers from London's Kingston University have begun a two-year study which could help prolong the lives of people with colorectal tumours.
Cancer 52 minutes ago | not rated yet | 0
Transformative research from Western University has identified new hormones in the body which may suppress breast cancer and stimulate the regression of breast tumors.
Cancer 1 hour ago | not rated yet | 0
(Medical Xpress)—Curtin University researchers have found evidence that targeting specific cells in the body can reverse the effects of cancer on the immune system.
Cancer 1 hour ago | 5 / 5 (1) | 0
A leading expert in childhood cancer at The University of Nottingham is spearheading a Europe-wide lobby of the European Parliament to try to make it easier for doctors to develop and test new treatments on children and young ...
Cancer 2 hours ago | not rated yet | 0
(AP)—Researchers examining the incidence of brain cancer at jet engine manufacturer Pratt & Whitney in Connecticut say they have found no statistically significant elevations in the rate of cancer among workers.
Cancer 3 hours ago | not rated yet | 0
(Medical Xpress)—A new study by researchers in the US has shown that an ancient virus can be modified to help in the fight against the simian immunodeficiency virus SIV, which is the equivalent in monkeys ...
1 hour ago | not rated yet | 0 |
How can healthy people who hear voices help schizophrenics? Finding the answer for this is at the centre of research conducted at the University of Bergen.
1 hour ago | 3 / 5 (1) | 0
New research presented today shows that formation of new neurons in the hippocampus - a brain region known for its importance in learning and remembering - could cause forgetting of old memories by causing a reorganization ...
42 minutes ago | not rated yet | 0
Ernie Pyle – an iconic war correspondent in World War II – reportedly said "There are no atheists in foxholes." A new joint study between two brothers at Cornell and Virginia Wesleyan found that only ...
45 minutes ago | not rated yet | 0
The individualisation of drug treatments to support patients to self-manage their conditions is a concept that sits at the heart of policy, but a recent study in BMJ Open shows that there is no concrete defini ...
1 hour ago | not rated yet | 0
Saudi Arabia said Friday it would send samples taken from animals possibly infected with a deadly SARS-like virus to the United States for testing in a bid to find the source of disease.
22 minutes ago | not rated yet | 0