Cancer stem cells use normal genes in abnormal ways

CDK1 is a "normal" protein -- its presence drives cells through the cycle of replication. And MHC Class I molecules are "normal" as well -- they present bits of proteins on the surfaces of cells for examination by the immune system. 

But a University of Colorado Cancer Center study published in the Journal Cancer Research shows that a population of cancer cells marked by MHC Class I molecules and high CDK1 is anything but normal. In fact, these MHC Class I-high, CDK1 high molecules may be at the heart of conditions including melanoma, pancreatic and colon cancers. These cells may, in fact, be the long-sought cancer stem cells that often resist treatments like chemotherapy to reseed these cancers once treatment ends.

From the outset, the goal of this study was different than most. Often, cancer researchers will grow tumors and then ask what kinds of drugs or genetic changes make tumors grow or shrink. However, the current study wondered not what makes tumors change size, but what factors in these cells initiate tumor growth in the first place. To answer this question, the study used patient samples, mouse models and publicly available genetic data to search for the genetic/genomic commonalities in cells capable of initiating melanoma, pancreatic and colon cancers.

The findings start with a molecule called MHC Class I, a common molecule that coats the outside of human cells and functions a bit like a hand waving a flag. When MHC Class I molecules wave "flags" (actually bits of proteins), that are not from host tissue, the immune system recognizes the cell as foreign and attacks it. For this reason, most cancer cells downregulate MHC as a way of evading the immune system.

But the current study shows that the population of cancer cells able to initiate the formation of new tumors does not downregulate MHC Class I molecules. In fact, if anything this special population of cancer cells upregulates MHC Class I molecules.

"Probably, these cells have another way to evade the immune system," says Mayumi Fujita, MD, PhD, Investigator at CU Cancer Center and Professor in the CU School of Medicine Departments of Dermatology and Immunology/Microbiology.

Oddly, this population of cancer cells that retains MHC Class I molecules also retains another feature of healthy cells, namely the presence of a protein called CDK1. CDK1 is a master regulator of the cell cycle -- with CDK1, cells progress through the cycle of replication; without CDK1, they do not. In this case, the more CDK1, the more able melanoma cells were to initiate new tumors.

"Our next question was why," Fujita says. "Why would CDK1 control not just the cell cycle, but also stem-ness?"

Finally, the answer includes something that is not "normal." Sox2 is a transcription factor that helps embryonic and neural stem cells keep their stem-ness. It is also a known marker of cancer stem cells, implicated in the development of more than 25 forms of the disease. Despite its identification as a driver of cancer, Sox2 remains a difficult target.

"It's very difficult to control a transcription factor like Sox2. We can show Sox2 is very important for tumorigenesis, but it's difficult to have a Sox2 inhibitor," Fujita says.

However, the current study found that CDK1 directly interacted with Sox2 to keep these cancer cells "stemmy." And here is the important part: "If CDK1 controls Sox2 function through this interaction, probably we can someday inhibit it, maybe through some way of targeting CDK1 or perhaps some way to interfere with the interaction of CDK1 with Sox2," Fujita says.

Importantly, this signature of MHC Class 1, CDK1 and Sox2 was common across melanoma, colon and pancreatic cancers, implying that cancer stem cells across cancer types may share common features.

"We can't say that all tumor types have this signature, but it's prevalent. We think probably this phenotype is very common in melanoma, pancreatic and colon cancer," Fujita says.

Moving forward, the Fujita group hopes to further define the mechanism of Sox2 regulation via CDK1 in hopes of finding essential links that might be targets for new drugs aimed, eventually, at stopping the action of Sox2.

We welcome researchers from different part of the world to submit your latest research at our upcoming conference "12th World Congress on Cell & Tissue Science" scheduled on March 11-12,2019 in Singapore which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more. For more info visit our conference website:Cell Tissue Science 2019

Combining genetic and sun exposure data improves skin cancer risk estimates

By combining data on individuals' lifetime sun exposure and their genetics, researchers can generate improved predictions of their risk of skin cancer.

Pierre Fontanillas, PhD, and colleagues at 23andMe, Inc., collected genetic and survey data from over 210,000 consented research participants of European descent. They analyzed the data to identify correlations between previously known and potentially novel skin cancer risk factors and the occurrence of three forms of skin cancer: melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Past studies had found that exposure to ultraviolet (UV) light increases skin cancer risk, as do other environmental factors such as living in a sunnier climate or at a higher altitude, and personal factors such as lighter skin pigmentation, higher numbers of moles on the skin, and family history of skin cancer.

"We aimed to validate previously known skin cancer risk factors in a large cohort, add detail to these and explore potential new ones, and find out whether and how these factors might interact with genetic risk," said Dr. Fontanillas.

They found that while each single factor was not particularly significant on its own, multiple factors could be combined into statistical models that were more informative. The best-performing models incorporated a genetic risk score composed of data on up to 50 genetic variants, along with survey data on family history, skin pigmentation and sensitivity, number of moles, estimated current sun exposure, sunbathing frequency before the age of 30, and body mass index (BMI).

The new models achieved a high predictive accuracy (area under the curve [AUC], between 0.81 and 0.85). Genetic factors alone accounted for 8.3 to 15.2 percent of the variance explained in skin cancer risk. Although the three skin cancers have different physiology, models did not find fundamental differences between the three cancer types, nor did they show strong interaction between genetic and environmental risk factors. While the self-reported nature of the survey data permitted researchers to collect a large dataset, it also presented some challenges, Dr. Fontanillas noted.

"Measuring lifetime exposure is generally challenging. It is particularly hard to capture sun exposure and when in life it happened, and it may be that some of the other correlates we found, like higher BMI, reflect a lack of outdoor activity rather than being directly correlated with risk of skin cancer," he said.

Moving forward, the researchers plan to expand their sample to groups with non-European ancestry and are exploring additional methods of calculating genetic risk score and measuring sun exposure. They hope to eventually obtain risk estimates accurate enough to be used by individuals and clinicians.

We welcome researchers from different part of the world to submit your latest research at our upcoming conference "12th World Congress on Cell & Tissue Science" scheduled on March 11-12,2019 in Singapore which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more. For more info visit our conference website:Cell Tissue Science 2019

Stem cell proliferation is controlled directly by nervous system, scientists find

University of Illinois neuroscientists, they represent untapped potential.For example, Somatic stem cells are microscopic workhorses, constantly regenerating cells throughout the body: skin and the lining of the intestine .

"If we could find a way to target and control stem cell proliferation in the body, there could be potential medical benefits, including turning off the proliferation of cancer stem cells or inducing proliferation of somatic stem cells where we want to grow tissue," says Elizabeth Davis, Doctoral Researcher, Neuroscience Program ,University of Illinois ."She says that for the first time, that stem cell proliferation is directly controlled by the autonomic nervous system (ANS)".

The ANS controls all of our unconscious functions: breathing, blood flow, digestion, and so forth. Its two major networks of nerve fibers run from the brain through the entire body, with neurons reaching into nearly every organ. These neurons release chemicals called neurotransmitters, which can affect target cells directly or indirectly.

When neurotransmitters bind to receptors in the membranes of certain cells, they elicit a direct response within the cell. But changes in cells can also occur when neurotransmitters induce a general state of inflammation or alter blood flow, an indirect route of action for the ANS.

"If you wanted to change the regeneration potential of an organ, for example, you wouldn't have to stimulate or suppress the activity of those neurons. Instead, you could just figure out what neurotransmitters are controlling proliferation and then get that chemical to those stem cells with targeted drug delivery," says Megan Dailey, assistant professor in the Department of Animal Sciences at U of I. 

To characterize the relationship, the researchers focused on stem cells in the intestinal lining, or epithelium, in mice. They found not only that the stem cells did have receptors for ANS neurotransmitters, but also the neurotransmitters changed the behavior of the cells -- just what they would expect to see for a direct relationship.

"We knew that nerves of the ANS came into close contact with cells of the intestinal epithelium, including stem cells, but we didn't know if the neurotransmitters were able to bind to the stem cells. When we isolated the stem cells and found there were actually ANS neurotransmitter receptors, we found that missing piece," Davis says.

To demonstrate that stem cell behavior was changing as a result of ANS stimulation, the researchers grew intestinal epithelial cells in the lab and exposed them to high levels of two neurotransmitters, norepinephrine and acetylcholine. Norepinephrine is a major neurotransmitter of the sympathetic nervous system, or "fight or flight" branch of the ANS, while acetylcholine is produced by the parasympathetic nervous system, or "rest and digest" branch.

"When we simulated activation of either of those systems, we saw a decrease in stem cell proliferation," Dailey says.

She suggests the body may avoid putting energy into making new cells when the fight or flight system is active. Instead, she reasons, that energy is needed to make a quick getaway. Peak moments of rest and digest may not be the best for making new cells, either, because when food is coming in, cellular processes related to digestion can create free radicals that can damage new cells.

"In neuroscience, people don't see the ANS as flashy or exciting, but these nerves are reaching so many cells in the body, including stem cells," Davis says. "Why would those nerves communicate with stem cells if they weren't doing anything? What if there's this big, exciting idea that we could use the nervous system to control stem cells?"

Dailey adds, "The ANS isn't controlled by itself -- it's controlled by the brain and the central nervous system. We think the brain is controlling the regeneration of all these tissues through the ANS. But that brings up a bigger picture. For individuals under severe depression or PTSD, for example, you see degeneration of some of their organs. It could be some sort of stress-related effect through the ANS decreasing the regenerative potential of the organs. Based on our findings, it looks like there could be a direct effect."

We welcome researchers from different part of the world to submit your latest research at our upcoming conference "12th World Congress on Cell & Tissue Science" scheduled on March 11-12,2019 in Singapore which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more. For more info visit our conference website:Cell Tissue Science 2019

Researchers develop 3D printed objects that can track and store how they are used

Cheap and easily customizable, 3-D printed devices are perfect for assistive technology, like prosthetics or "smart" pill bottles that can help patients remember to take their daily medications.

Researchers at the University of Washington have developed 3D printed assistive technology that can track and store their use — without using batteries or electronics. Credit: Mark Stone/University of Washington

But these plastic parts don't have electronics, which means they can't monitor how patients are using them. Now engineers at the University of Washington have developed 3-D printed devices that can track and store their own use -- without using batteries or electronics. Instead, this system uses a method called backscatter, through which a device can share information by reflecting signals that have been transmitted to it with an antenna.

"We're interested in making accessible assistive technology with 3-D printing, but we have no easy way to know how people are using it," said co-author Jennifer Mankoff, Professor, UW's Paul G. Allen School of Computer Science & Engineering. "Could we come up with a circuitless solution that could be printed on consumer-grade, off-the-shelf printers and allow the device itself to collect information? That's what we showed was possible in this paper."

Previously the team developed the first 3-D printed objects that connect to Wi-Fi without electronics. These purely plastic devices can measure if a detergent bottle is running low and then automatically order more online.

"Using plastic for these applications means you don't have to worry about batteries running out or your device getting wet. That can transform the way we think of computing," said Shyam Gollakota, Associate Professor, Allen School. "But if we really want to transform 3-D printed objects into smart objects, we need mechanisms to monitor and store data."

The researchers tackled the monitoring problem first. In their previous study, their system tracks movement in one direction, which works well for monitoring laundry detergent levels or measuring wind or water speed. But now they needed to make objects that could monitor bidirectional motion like the opening and closing of a pill bottle.

"Last time, we had a gear that turned in one direction. As liquid flowed through the gear, it would push a switch down to contact the antenna," said lead author Vikram Iyer, Doctoral Student, UW Department of Electrical & Computer Engineering. "This time we have two antennas, one on top and one on bottom, that can be contacted by a switch attached to a gear. So opening a pill bottle cap moves the gear in one direction, which pushes the switch to contact one of the two antennas. And then closing the pill bottle cap turns the gear in the opposite direction, and the switch hits the other antenna."

Both of the antennas are identical, so the team had to devise a way to decode which direction the cap was moving.

"The gear's teeth have a specific sequencing that encodes a message. It's like Morse code," said co-author Justin Chan, Doctoral Student, Allen School. "So when you turn the cap in one direction, you see the message going forward. But when you turn the cap in the other direction, you get a reverse message."

In addition to tracking, for example, pill bottle cap movement, this same method can be used to monitor how people use prosthetics, such as 3-D printed e-NABLE arms. These mechanical hands, which attach at the wrist, are designed to help children with hand abnormalities grasp objects. When children flex their wrists, cables on the hand tighten to make the fingers close. So the team 3-D printed an e-NABLE arm with a prototype of their bidirectional sensor that monitors the hand opening and closing by determining the angle of the wrist. The researchers also wanted to create a 3-D printed object that could store its usage information while out of Wi-Fi range. For this application, they chose an insulin pen that could monitor its use and then signal when it was getting low.

"You can still take insulin even if you don't have a Wi-Fi connection," Gollakota said. "So we needed a mechanism that stores how many times you used it. Once you're back in the range, you can upload that stored data into the cloud."

This method requires a mechanical motion, like the pressing of a button, and stores that information by rolling up a spring inside a ratchet that can only move in one direction. Each time someone pushes the button, the spring gets tighter. It can't unwind until the user releases the ratchet, hopefully when in range of the backscatter sensor. Then, as the spring unwinds, it moves a gear that triggers a switch to contact an antenna repeatedly as the gear turns. Each contact is counted to determine how many times the user pressed the button. These devices are only prototypes to show that it is possible for 3-D printed materials to sense bidirectional movement and store data. The next challenge will be to take these concepts and shrink them so that they can be embedded in real pill bottles, prosthetics or insulin pens, Mankoff said.

"This system will give us a higher-fidelity picture of what is going on," she said. "For example, right now we don't have a way of tracking if and how people are using e-NABLE hands. Ultimately what I'd like to do with these data is predict whether or not people are going to abandon a device based on how they're using it."

We welcome researchers from different part of the to submit abstract on their latest research at our upcoming conference Cell Tissue Science 2019 which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more.We welcome you to the our upcoming conference “ 12th World Congress on Cell & Tissue Science” . For more info visit :Cell Tissue Science 2019