Squamous cell cancers of the oral cavity and esophagus are common throughout the world, with over 650,000 cases of oral cancer each year and esophageal cancer representing the sixth most common cause of cancer death in men. Research by University of Pennsylvania School of Medicine investigators has shown that a protein that helps cells stick together is frequently absent or out of place in these cancers, but it's unclear if its loss causes the tumors.
The investigators report that mice engineered to lack this protein, called p120-catenin (p120ctn), in the oral-upper digestive tract develop squamous cell cancers. The data, reported Cancer Cell, settle a 20-year debate and prove that p120ctn is a tumor-suppressor protein. What's more, the tumors that form in this mouse model closely resemble human disease and may point the way to novel therapies and early detection strategies.
"As the mice aged, what we saw was a dramatic evolution of precancer to cancer," says senior author Anil K. Rustgi, MD, the T. Grier Miller Professor of Medicine and Genetics and chief of Gastroenterology. "Both the precancerous growth, called dysplasia, and the cancer look exactly like what we see in humans. This is really exciting because it supports efforts for prevention and early detection, especially in people who drink alcohol and smoke cigarettes excessively and are at high risk for the disease in many regions of the world."
In healthy tissues, p120ctn is part of a protein complex that holds epithelial cells in tightly packed sheets. When p120ctn (or another of these cell adhesion proteins) is lost, a wide variety of cancers including those in prostate, breast, pancreas, colon, skin, bladder, and the endometrium, can result.
The cells lose their tight cell-cell contacts and can migrate more easily, which likely favors cancer spread and invasion of new cells. However, earlier attempts to test the effects of p120ctn loss on cancer formation were derailed because the animals cannot survive throughout embryonic development or immediately after birth without the protein.
To get around that problem, Rustgi and colleagues used a system called Cre-Lox that allows them to remove a particular gene in only a subset of tissues. In this case, the team deleted p120ctn from the oral cavity, esophagus and forestomach. The mutant animals survived through early development and birth, but by 4 to 6 months, most of the mutant animals had developed precancerous lesions and by 9 to 12 months, 70 percent of the mutant animals had full blown tumors. By contrast, none of the control littermates developed cancer.
The investigators noted that as the lesions developed, the tumor cells secreted inflammatory signals that acted like homing signals for immune cells called immature myeloid cells. These cells, in turn, helped to create a microenvironment that supported tumor growth. In fact, when the researchers blocked recruitment of the immune cells, they saw a dramatic reduction in tumor invasion.
Based on these observations, Rustgi thinks that targeting the immature myeloid cells may reverse or slow tumor grown in humans, although more work needs to be done in animal models before the approach is tested in the clinic.
Rustgi says that the mouse model will help test innovative therapies and early detection tests. He says that although he was born and raised in the United States, he was influenced by five years he spent as a child in India, where oral cancer is common due to the proportion of the population that chews betel nuts. "I remember, even as a little kid, I would see people with oral lesions," he says. "I didn't know what they were then, but it has always motivated me at a personal level. Esophageal cancer biology has also been a long-standing interest of mine because it affects so many underserved people in the inner cities in the United States."
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University of Pennsylvania School of Medicine: http://www.uphs.upenn.edu/news/
Thanks to University of Pennsylvania School of Medicine for this article.
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David Summers, a 37 year old MS patient from Murfreesboro, Tennessee was a score of 8.0 on the Expanded Disability Status Scale (EDSS) when he had the Combination Liberation Therapy and Stem Cell Transplantation at CCSVI Clinic in March of 2012. Having been diagnosed in 1996 he had been in a wheelchair for the past decade without any sensation below the waist or use of his legs.
“It was late 2011 and I didn’t have much future to look forward to” says David. “My MS was getting more progressive and ravaging my body. I was diagnosed as an 8.0 on the EDSS scale; 1 being mild symptoms, 10 being death. There were many new lesions on my optic nerves, in my brain and on my spinal cord. My neurologist just told me: ‘be prepared to deteriorate’. I knew that he was telling me I didn’t have much time left, or at least not much with any quality.” David had previously sought out the liberation therapy in 2010 and had it done in a clinic in Duluth Georgia. “The Interventional Radiologist who did it told me that 50% of all MS patients who have the jugular vein-clearing therapy eventually restenose. I didn’t believe that would happen to me if I could get it done. But I have had MS for 16 years and apparently my veins were pretty twisted up”. Within 90 days, David’s veins had narrowed again, and worse, they were now blocked in even more places than before his procedure.
“I was so happy after my original procedure in 2010. I immediately lost all of the typical symptoms of MS. The cog fog disappeared, my speech came back, the vision in my right eye improved, I was able to regulate my body temperature again, and some of the sensation in my hands came back. But as much as I wanted to believe I felt something, there was nothing below the waist. I kind of knew that I wouldn’t get anything back in my legs. There was just way too much nerve damage now”. But any improvements felt by David lasted for just a few months.
After his relapse, David and his family were frustrated but undaunted. They had seen what opening the jugular veins could do to improve him. Because the veins had closed so quickly after his liberation procedure, they considered another clinic that advocated stent implants to keep the veins open, but upon doing their due diligence, they decided it was just too risky. They kept on searching the many CCSVI information sites that were cropping up on the Internet for something that offered more hope. Finding a suitable treatment, especially where there was no known cure for the disease was also a race against time. David was still suffering new attacks and was definitely deteriorating. Then David’s mother Janice began reading some patient blogs about a Clinic that was offering both the liberation therapy and adult autologous stem cell injections in a series of procedures during a hospital stay. “These patients were reporting a ‘full recovery’ of their neurodegenerative deficits” says Janice, “I hadn’t seen anything like that anywhere else”. She contacted CCSVI Clinic in late 2011 and after a succession of calls with the researchers and surgeons they decided in favor of the combination therapies.
“I went to CCSVI Clinic in India without knowing what to expect” says David, “but I basically had one shot left and this was it. I was becoming pretty disabled, and I couldn’t think very clearly”. David was triaged with a clinic intake of other MS patients and had the liberation therapy on March 27, 2012. They also drew bone marrow from his hip bone in the same procedure. When he woke up from the procedure, he again felt the immediate effect of the widening of the veins. “In case anyone doesn’t believe that the liberation therapy works, I can tell them that this is much more than placebo effect.” The MS symptoms described earlier again disappeared. Four days later he had the first of the stem cell injections from the cultured cells taken from his hip bone during the liberation therapy. The first transplant was injected into the area just below his spine. Over the next 4 days he would receive about 100 million stem cells cultured in specific growth factors for differentiated effect.
He was not quite prepared for what happened next. A few hours after the first transplant, he was taken back into his hospital room and was transferred to the hospital bed. “I’m not completely helpless when it comes to moving from a chair or a bed”, says David, “One of the things I can do for myself is to use my arms to throw my leg into a position to be able to shift the rest of my body weight over to where I’m going. But this time to my amazement, I didn’t have to pick up the dead weight of my leg and throw it. It moved on its own, exactly where my brain told it to go”. Shortly after his first stem cell transplant procedure, some motor function in his lower body had returned. “This was the first time in 10 years I had any sensation or motor function below my waste so it was quite a shock.”
In the next month, most every motor nerve and body function has either returned or is on its way to recovery. “It’s been over a decade since I’ve had any power over my elimination functions. Now it’s all come back. I have total bladder control”. He’s also working out every day, following the physiotherapy routine given him by the clinic. “For years, I haven’t been able to work out without getting sick for a couple of days afterward. Now I have muscles popping out all over the place where I haven’t seen them since my MS became progressive…and I can work out as hard or as much as I want. With my ability to do the hard work my balance is improving each day and I’m able to take steps unassisted. I’m definitely going to be coming all the way back.”
Dr. Av Gupte, the neurosurgeon who has now done over 2000 adult autologous stem cell transplants for various neurologic disease conditions says that the stem cells in David’s body will continue to work their healing process for the next year. “With the incredible progress I’ve seen so far, I won’t need a year”, says David. “It’s only been a little over two months and I have most everything back. I can’t wait to get up each day to check out my improvements. My right hand is completely back to normal without any numbness and the left is on its way. I have good strength in my legs now and I’m working on the balance”.
Other MS patients treated with the combination therapy over the past 18 months have seen similar improvements but none have been as disabled as David. “If I can come back from where I was, most everyone with MS could too. For me, CCSVI Clinic has been my miracle and I can’t say enough about the doctors, researchers and staff who are helping me to recover. For me, MS was my previous diagnosis”.For more information please visit http://www.ccsviclinic.ca/?p=904
Chronic cerebrospinal venous insufficiency (CCSVI), or the pathological restriction of venous vessel discharge from the CNS has been proposed by Zamboni, et al, as having a correlative relationship to Multiple Sclerosis. From a clinical perspective, it has been demonstrated that the narrowed jugular veins in an MS patient, once widened, do affect the presenting symptoms of MS and the overall health of the patient. It has also been noted that these same veins once treated, restenose after a time in the majority of cases. Why the veins restenose is speculative. One insight, developed through practical observation, suggests that there are gaps in the therapy protocol as it is currently practiced. In general, CCSVI therapy has focused on directly treating the venous system and the stenosed veins. Several other factors that would naturally affect vein recovery have received much less consideration. As to treatment for CCSVI, it should be noted that no meaningful aftercare protocol based on evidence has been considered by the main proponents of the ‘liberation’ therapy (neck venoplasty). In fact, in all of the clinics or hospitals examined for this study, patients weren’t required to stay in the clinical setting any longer than a few hours post-procedure in most cases. Even though it has been observed to be therapeutically useful by some of the main early practitioners of the ‘liberation’ therapy, follow-up, supportive care for recovering patients post-operatively has not seriously been considered to be part of the treatment protocol. To date, follow-up care has primarily centered on when vein re-imaging should be done post-venoplasty. The fact is, by that time, most patients have restenosed (or partially restenosed) and the follow-up Doppler testing is simply detecting restenosis and retrograde flow in veins that are very much deteriorated due to scarring left by the initial procedure. This article discusses a variable approach as to a combination of safe and effective interventional therapies that have been observed to result in enduring venous drainage of the CNS to offset the destructive effects of inflammation and neurodegeneration, and to regenerate disease damaged tissue.
As stated, it has been observed that a number of presenting symptoms of MS almost completely vanish as soon as the jugulars are widened and the flows equalize in most MS patients. Where a small number of MS patients have received no immediate benefit from the ‘liberation’ procedure, flows in subject samples have been shown not to have equalized post-procedure in these patients and therefore even a very small retrograde blood flow back to the CNS can offset the therapeutic benefits. Furthermore once the obstructed veins are further examined for hemodynamic obstruction and widened at the point of occlusion in those patients to allow full drainage, the presenting symptoms of MS retreat. This noted observation along with the large number of MS patients who have CCSVI establish a clear association of vein disease with MS, although it is clearly not the disease ‘trigger’.For more information please visit http://www.ccsviclinic.ca/?p=978