Pancreatic cancer has a grim prognosis. It is usually detected after the disease has spread, and chemotherapy tends to do little to slow the cancer's growth. Even with treatment, most patients live only about six months after they are diagnosed with the disease.
Researchers at Cold Spring Harbor Laboratory (CSHL) think it's possible to do better with a different type of treatment. Part of the problem, they say, is that cancer cells in the pancreas are protected by the dense matrix that surrounds them. The matrix is a mixture of extracellular components and noncancerous cells known as the stroma. All solid tumors contain stroma. In pancreatic cancers, this fibrous material is particularly abundant, making up nearly 90 percent of a tumor's mass. This stroma impedes anticancer drugs' from getting to their targets. Additionally, stromal cells secrete factors that actually help the tumors grow.
Overcoming the stroma's protective influence has been challenging, but new leads from the research team, as reported on October 26, 2018 in the journal Cancer Discovery, point to a promising strategy. In fact, the new findings suggest that drugs which target the right cellular pathways can do more than just thwart tumor-supporting cells in the stroma. They may recruit them into the anticancer fight.
A key element of the stroma is a type of cell called a fibroblast. Fibroblasts manufacture the stroma's connective tissue. They also generate factors that promote cancer cell growth and prevent the immune system from attacking the cancerous cells. Last year the research team discovered that the stroma of pancreatic tumors contains at least two types of fibroblasts. One type show features known to support tumor growth, the other type appear to have the opposite effect.
The good news is that the fibroblasts' identities are not fixed. With the right cues, tumor-promoting fibroblasts can become tumor-restrictors.
"These cells can convert into one another, depending on the cues they get from the microenvironment and from the cancer cells," explains an expert, a postdoctoral researcher in the research lab who led the new study. "This is potentially useful because, in theory, you can shift the tumor-promoting cells to tumor-restraining, rather than just depleting the tumor-promoting cells."
In this new report, an expert and their colleagues have identified specific molecular signals released by cancer cells that determine fibroblasts' character within pancreatic tumors. They have discovered that one such molecule, IL-1, drives fibroblasts to take on a tumor-promoting identity. They have also shown how another molecule, TGF-beta, overrides that signal and keeps fibroblasts in a potentially anticancer state even when IL-1 is present.
The researchers are now exploring what happens to pancreatic tumors when they manipulate IL-1 and TGF-beta signaling and convert tumor-promoting fibroblasts to a more beneficial state. They will also investigate what happens when they target these pathways in combination with chemotherapy or cancer immunotherapies. Ultimately, the expert says, patients may benefit most from a combination of therapies that target both the cancer cells and parts of the microenvironment that support their growth.
The National Toxicology Program (NTP) concluded there is clear evidence that male rats exposed to high levels of radio frequency radiation (RFR) like that used in 2G and 3G cell phones developed cancerous heart tumors, according to final reports released today. There was also some evidence of tumors in the brain and adrenal gland of exposed male rats. For female rats, and male and female mice, the evidence was equivocal as to whether cancers observed were associated with exposure to RFR. The final reports represent the consensus of NTP and a panel of external scientific experts who reviewed the studies in March after draft reports were issued in February.
"The exposures used in the studies cannot be compared directly to the exposure that humans experience when using a cell phone," said John Bucher, Ph.D., NTP senior scientist. "In our studies, rats and mice received radio frequency radiation across their whole bodies. By contrast, people are mostly exposed in specific local tissues close to where they hold the phone. In addition, the exposure levels and durations in our studies were greater than what people experience."
The lowest exposure level used in the studies was equal to the maximum local tissue exposure currently allowed for cell phone users. This power level rarely occurs with typical cell phone use. The highest exposure level in the studies was four times higher than the maximum power level permitted.
"We believe that the link between radio frequency radiation and tumors in male rats is real, and the external experts agreed," said Bucher.
The $30 million NTP studies took more than 10 years to complete and are the most comprehensive assessment, to date, of health effects in animals exposed to RFR with modulations used in 2G and 3G cell phones. 2G and 3G networks were standard when the studies were designed and are still used for phone calls and texting.
"A major strength of our studies is that we were able to control exactly how much radio frequency radiation the animals received -- something that's not possible when studying human cell phone use, which has often relied on questionnaires," said Michael Wyde, Ph.D., lead toxicologist on the studies.
He also noted the unexpected finding of longer lifespans among the exposed male rats. "This may be explained by an observed decrease in chronic kidney problems that are often the cause of death in older rats," Wyde said.
The animals were housed in chambers specifically designed and built for these studies. Exposure to RFR began in the womb for rats and at 5 to 6 weeks old for mice, and continued for up to two years, or most of their natural lifetime. The RFR exposure was intermittent, 10 minutes on and 10 minutes off, totaling about nine hours each day. RFR levels ranged from 1.5-6 watts per kilogram in rats, and 2.5-10 watts per kilogram in mice.
These studies did not investigate the types of RFR used for Wi-Fi or 5G networks.
"5G is an emerging technology that hasn't really been defined yet. From what we currently understand, it likely differs dramatically from what we studied," said Wyde.
For future studies, NTP is building smaller RFR exposure chambers that will make it easier to evaluate newer telecommunications technologies in weeks or months, rather than years. These studies will focus on developing measurable physical indicators, or biomarkers, of potential effects from RFR. These may include changes in metrics like DNA damage in exposed tissues, which can be detected much sooner than cancer.
The U.S. Food and Drug Administration nominated cell phone RFR for study by NTP because of widespread public use of cell phones and limited knowledge about potential health effects from long-term exposure. NTP will provide the results of these studies to FDA and the Federal Communications Commission, who will review the information as they continue to monitor new research on the potential effects of RFR.
The team from the Cancer Research UK (CRUK) Beatson Institute also found it could make chemotherapy more effective against some tumours.
They carried out their experiments on mice but say it could one day lead to human treatment.
The Glasgow study may point to a way of "starving" cancerous cells.
Every cell in our bodies feeds on the sugar glucose. Tumour cells consume even more.
The team of Glasgow University, fed mice with tumours another sugar called mannose.
Mannose occurs naturally in many fruits. It is also made in some cells in our bodies.
Its molecular structure is very nearly identical to that of glucose but the tiny difference seems to hold a crucial key.
The mice had different types of tumours. Some were given mannose three times a week through a feeding tube. Others got it continuously in their drinking water.
Writing in the journal Nature, team report the mice showed no obvious side effects from the mannose. More importantly, the sugar appeared to reduce significantly the growth of some kinds of tumours.
The process was repeated, this time with the widely-used chemotherapy drugs cisplatin and doxorubicin to see if mannose increased their effectiveness. In some cases, tumour growth appeared to slow and the lifespans of some mice actually increased.
Acetylsalicylic acid, best known as aspirin, and omega-3 fatty acids support various aspects of health, and scientists continue to uncover how these substances work. One recent study suggests that both could have an impact on colon cancer risk.
The National Cancer Institute estimate that doctors will diagnose around 140,250 new cases of cancer of the colon and rectum in 2018 in the United States.
Colon cancer develops from polyps or abnormal growths of tissue within the colon. Many of these polyps are benign, but some can lead to cancerous tumors.
Doctors identify precancerous polyps through colonoscopies that allow them to detect visible abnormalities in the large bowel.
In a new clinical trial, dubbed the Sea Food Trial, specialists from the universities of Leeds, Nottingham, Bradford, and Newcastle in the United Kingdom, in collaboration with researchers from other institutions, made an intriguing find.
They wanted to see if widely available drugs, such as aspirin and eicosapentaenoic acid (EPA) — one of the key fatty acids contained by omega-3 — would reduce the number of precancerous bowel polyps in people at high risk of colon cancer.
Scientists have equipped a virus that kills carcinoma cells with a protein so it can also target and kill adjacent cells that are tricked into shielding the cancer from the immune system.
It is the first time that cancer-associated fibroblasts within solid tumours - healthy cells that are tricked into protecting the cancer from the immune system and supplying it with growth factors and nutrients - have been specifically targeted in this way.
The researchers, who were primarily funded by the Medical Research Council (MRC) and Cancer Research UK, say that if further safety testing is successful, the dual-action virus - which they have tested in human cancer samples and in mice - could be tested in humans with carcinomas as early as next year.
Currently, any therapy that kills the 'tricked' fibroblast cells may also kill fibroblasts throughout the body - for example in the bone marrow and skin - causing toxicity.
In this study, published in the journal Cancer Research, the researchers used a virus called enadenotucirev, which is already in clinical trials for treating carcinomas. It has been bred to infect only cancer cells, leaving healthy cells alone.
They added genetic instructions into the virus that caused infected cancer cells to produce a protein called a bispecific T-cell engager.
The protein was designed to bind to two types of cells and stick them together. In this case, one end was targeted to bind to fibroblasts. The other end specifically stuck to T cells - a type of immune cell that is responsible for killing defective cells. This triggered the T cells to kill the attached fibroblasts.
Until now, there has not been any way to kill both cancer cells and the fibroblasts protecting them at the same time, without harming the rest of the body.
"Our new technique to simultaneously target the fibroblasts while killing cancer cells with the virus could be an important step towards reducing immune system suppression within carcinomas and should kick-start the normal immune process.
"These viruses are already undergoing trials in people, so we hope our modified virus will be moving towards clinical trials as early as next year to find out if it is safe and effective in people with cancer."
The scientists successfully tested the therapy on fresh human cancer samples collected from consenting patients, including solid prostate cancer tumours which reflect the complex make-up of real tumours. They also tested the virus on samples of healthy human bone marrow and found it did not cause toxicity or inappropriate T cell activation.
Further clinical studies will be crucial to determine that the stimulation of the patient's immune system does not produce unintended consequences".
The next stage will be using clinical trials to test whether this is both a safe and effective way to treat the disease in people."
The virus targets carcinomas, which are the most common type of cancer and start in cells in the skin or in tissues that line or cover internal organs, such as the pancreas, colon, lungs, breasts, ovaries and prostate.