New Research on Sperm Stem Cells has Implications for Male Infertility and Cancer

New research from scientists at Huntsman Cancer Institute (HCI) at the University of Utah and collaborators at University of Utah Health (U of U Health) sheds light on the complex process that occurs in the development of human sperm stem cells. This is the first study to characterize the changes human sperm stem cells undergo as they mature. The results have implications for understanding male infertility as well as cancer development and were published today in the journal Cell Stem Cell.

Previous studies of sperm stem cells have been limited to model systems, including mice. But this first study of developing human sperm stem cells revealed this process was much more complex in humans than had been previously understood. Using genome analysis tools, scientists outlined the multistage process that sperm stem cells undergo during their normal development.

“This information yields new insights into how sperm stem cells function and develop under normal circumstances,” says the study’s lead author Bradley Cairns, PhD, senior director of basic science at HCI and professor and chair of oncological sciences at the U of U. “We have built a very important framework we can now use to help us understand what happens when things go wrong, resulting in issues like infertility and cancer in men.”

In the study, scientists examined all of the genes that turn ‘on’ or ‘off’ in any given cell during normal development. Using single cell RNA sequencing analysis, the Cairns lab profiled cells individually, establishing the gene expression profile in human sperm stem cells.

Their findings outlined four distinct cellular phases of sperm stem cells maturation, revealing how the stem cells progress from a “quiescent” state, to a “proliferation” state during which stem cells divide, to a final “differentiation” state when stem cells mature to become sperm. Specifically, the data reveal distinct transitions in factors that influence the different cellular states including cell cycle regulators, transcription factors, and signaling factors.

“Working with my patients with infertility, I have seen how devastating this diagnosis can be,” says co-author and reproductive urologist James Hotaling, MD, also an assistant professor of surgery at U of U Health. “This study will help us understand what causes infertility in some cases.”

The results may also have implications for understanding how some cancers arise. Men with infertility are known to be at higher risk for certain cancers including testicular and prostate cancers. “Our study sheds new light on how genes normally function in sperm stem cells,” says Cairns. “The next steps will be to use this knowledge to better understand what changes happen when sperm stem cells don’t develop normally and instead convert into cancer cells.”

The authors believe the results of the study could lead to better tools for diagnosing and treating patients with male infertility, as well as uncovering the complicated genetic changes that underlie cancers associated with male infertility.

Cairns and Hotaling collaborated with first author Jingtao Guo and co-authors Edward Grow, Chongil Yi, Patrick Murphy, Candice Wike, and Douglas Carrell. The research is titled “Transcription, Signaling and Metabolic Transitions During Human Spermatogonial Stem Cell Differentiation”.

This study was funded by the National Institutes of Health/National Cancer Institute P30 CA042014, the Howard Hughes Medical Institute, the University of Utah, and the Huntsman Cancer Foundation.

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gene slicing, doctor

Huntsman Cancer Institute’s Researchers Develop New Method for Gene Silencing

A new study highlights a new research method using the recently developed CRISPR technique. In short, CRISPR is a technology that allows researchers to cut out a section of DNA that causes a disease, like cancer, and then replace the section with normal, healthy genes.

Jay Gertz, PhD, a researcher at Huntsman Cancer Institute (HCI) at the University of Utah and his team have developed a new technique involving CRISPR. But instead of cutting out certain sections of DNA, this new technique blocks other things from binding to the DNA, including proteins such as estrogen receptor, which is a key driver in the development of breast and uterine cancers.

“With this technique, we are targeting regions of the genome, called enhancers, which are really important in turning genes on and turning genes off and play a key role in cancer development,” said Gertz. “These areas are challenging to study, and this new technique allows us to study these difficult regions of DNA in a flexible and fast way.”

HCI researchers can now target multiple sites of the genome simultaneously and trigger them to become inactive. That will make it harder for proteins like estrogen receptor to bind the genome and drive tumor growth.

“This technique we have developed is basically putting a stop sign down at a specific place in the genome. This is a great way to non-invasively see what a piece of DNA is doing,” said Julia Carleton, HCI researcher and lead author on the paper. “With this process, we are trying to see which pieces of DNA that are bound by the estrogen receptor are important for controlling genes that are turned on during an estrogen response.”

The Gertz lab recently received a $3M grant from the National Human Genome Research Institute to support this research and expand their work to a larger set of genes, which will allow them to uncover the underlying principles of how estrogen receptor works in breast and uterine cancers and how these enhancers are playing a role in cancer.

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Huntsman Cancer Institute Study Identifies Enhanced Impact of Treatment for Hereditary Cancer Patients

People with an inherited syndrome called familial adenomatous polyposis (FAP) have a 100% lifetime risk of developing colorectal cancer if they do not seek appropriate medical care. Recent findings published by researchers at Huntsman Cancer Institute at the University of Utah identified a promising prevention treatment for patients with FAP. A new study takes these findings a step further by reporting that the treatment led to a near-complete blockade of cancer growth pathways in polyps isolated from FAP patients. Further, these patients showed evidence of activated immune responses aimed at destroying pre-cancerous polyps. The findings were published today in the journal Cancer Prevention Research.

FAP is an inherited disorder that occurs in about 1 in 10,000 people. Patients with FAP develop hundreds to thousands of precancerous growths called polyps in their large and small intestine. Many of these people choose to have surgery to remove their colon, but they may still develop polyps in their small intestine. The prior HCI study identified a two-drug combination of sulindac and erlotinib which significantly reduced precancerous polyps in FAP patients.

Scientists at HCI have further developed these findings. They conducted genomic analyses of polyps collected from FAP patients who participated in the trial. A comparison of gene expression in tissue from patients who received the treatment versus those who did not revealed that the drug combination led to a near complete blockage of pathways involved in polyp growth. Additionally, the scientists observed activation of immune pathways in polyps from treated FAP patients. These findings suggest that the sulindac-erlotinib treatment activated natural defense responses aimed at polyp eradication.

Deborah Neklason, PhD, an investigator at HCI and research associate professor of Internal Medicine at the University of Utah, led the study. Neklason was surprised to see the immune response to the polyps in these patients. According to Neklason, “We thought treating the patients with this combination of drugs would stop the polyps from growing, and stop new polyps from developing. But what we actually saw was polyps shrinking. We saw them start to go away,” said Neklason.

Don Delker, PhD, research assistant professor of Internal Medicine at the University of Utah oversaw the genomic analysis performed on the samples. “It was encouraging to see such a strong response in these tissues and the blocking of pathways from which cancer develops. We hope to use this information to help us find better treatments for patients with precancerous growths that can develop from these pathways.”

The researchers are encouraged by these results and the potential for this information to help address an unmet clinical need in patients with FAP who develop cancers of the small intestine as very limited treatment options are available to them.

The next step is to identify optimal dosing of the drug combination. To achieve this, scientists and clinicians at HCI, The Mayo Clinic, and other Cancer Centers are planning to conduct additional clinical studies in FAP patients.

The study was funded by the National Institutes of Health HHSN2612012000131, National Cancer Institute P30 CA042014, P01 CA073992, and National Center for Advancing Translational Sciences UL1TR00106; and the Huntsman Cancer Foundation.

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Liver Cancer: Are You at Risk?

Liver cancer can be hard to find early. Signs of liver cancer may not show up until the disease has progressed and is harder to treat. It’s important to know if you are at risk for liver cancer and be aware of signs of the disease.

Early detection is the key to having the best possible outcome with any ailment, including liver cancer, says Robin Kim, MD, a Huntsman Cancer Institute (HCI) researcher and a liver transplant surgeon at University of Utah Health.

Liver Cancer Risk Factors

Liver, healthy and cirrhosis
Anything that increases your chance of getting a disease is called a risk factor. Certain risk factors make some people more likely to develop liver cancer. Having a risk factor does not mean that you will get cancer, and not having risk factors doesn’t mean that you will not get cancer. Be sure to tell your doctor if you have any of these risk factors for liver cancer:

Hepatitis B or Hepatitis C

Having both types of hepatitis raises the risk even more. The hepatitis B vaccine may help prevent liver cancer. The Centers for Disease Control and Prevention recommends that everyone get this vaccine. It is usually given at birth and completed at 6 months. Unvaccinated adults should talk to their doctor about getting the vaccine.

Cirrhosis

This can be caused by hepatitis (especially hepatitis C) or by drinking large amounts of alcohol for many years.
Metabolic syndrome, a set of conditions that occur together, including extra fat around the abdomen, high blood sugar, high blood pressure, high levels of triglycerides, and low levels of high-density lipoproteins in the blood. A liver injury that is long-lasting, especially if it leads to cirrhosis.

Hemochromatosis

Hemochromatosis, a condition in which the body takes up and stores more iron than it needs. The extra iron is stored in the liver, heart, and pancreas. Poisoning with aflatoxin, a fungus that can grow on foods such as grains and nuts that have not been stored properly.

Dr. Kim recommends that people who have liver disease work with a dedicated team of liver experts. “Such a team includes not only cancer providers but also liver specialists, who together can guide the patient through caring for his or her liver even before cancer might appear,” he says. Liver specialists can also recommend tests to look for liver cancer so it can be found as early as possible.

Signs of Possible Liver Cancer

Liver cancer can cause these symptoms:

  • A hard lump on the right side just below the rib cage
  • Discomfort in the upper abdomen on the right side
  • A swollen abdomen
  • Pain near the right shoulder blade or in the back
  • Jaundice (yellowing of the skin and whites of the eyes)
  • Easy bruising or bleeding
  • Nausea and vomiting
  • Loss of appetite or feelings of fullness after eating a small meal
  • Pale, chalky bowel movements and dark urine

Other conditions that are not serious can also cause these conditions. It is always best to check with your doctor if you have any unusual body changes that last longer than two weeks.

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New Study Finds Childhood Cancer Survivors Commonly Stay at Jobs to Keep Health Insurance

The results of a national cancer survey find a significant number of childhood cancer survivors are worried about keeping their health insurance, to the point of letting it affect their career decisions. The findings were published today in JAMA Oncology.

Anne Kirchhoff, PhD, an investigator at Huntsman Cancer Institute (HCI) and assistant professor of pediatrics at the University of Utah, led the study. Her goal was to examine the prevalence of job lock in full-time, employed childhood cancer survivors. Job lock is when an employee stays at a job in order to keep work-related health insurance.

The study found 23 percent of childhood cancer survivors reported job lock, compared to just under 17 percent of the survivors’ siblings who never had cancer.

“Even with protections and expansions of insurance coverage in the U.S., this study proves there is still quite a bit of worry about insurance,” says Kirchhoff, “and it’s affecting how people make decisions from a job standpoint. Employer-based insurance coverage is the most common way people get insurance in the U.S. If someone gets stuck in a certain job because they want to keep their insurance coverage, that could really affect their earning power across a lifetime. It could potentially stymie their ability to start a new company or take on a job that would allow them to have more career or income growth, all because of health insurance worries.”

The study found female survivors and survivors with chronic health conditions were more likely to report job lock. Researchers also determined survivors who had a history of problems paying medical bills and those with past health insurance denials were more likely to report feeling like they couldn’t change jobs because of insurance worries.

Kirchhoff says, “This information gives us a feel for high-risk groups of survivors who may need more information about insurance. Many people experience a gap in education and literacy around insurance, and it’s important for people to understand their options – even those who are employed and consistently had access to insurance through work. We want to know what their concerns are so we can help patients and survivors. Getting health care should not be a worry for cancer survivors.”

The study analyzed 394 pediatric cancer survivors from pediatric oncology institutions across the U.S., along with 128 of their siblings. All of the participants worked 35 hours or more per week. Eighty-eight percent of them had employer-sponsored health insurance. Only four percent of survivors (and just over six percent of siblings) were uninsured.

The cancer survivors were treated for cancer between birth and age 20, and all of the participants ranged in age at the time of the survey from their 20s to early 60s. They were asked to fill out surveys analyzing their insurance and work concerns.

Childhood cancer survivors were chosen to study because their life experiences are unique. Childhood cancer patients have seen tremendous growth in outcomes and survival over the years. But many times their strong treatments as children can lead to health problems as they get older. Certain chemotherapies can increase a patient’s risk of chronic health problems, such as cardiovascular disease, down the road. Treatments can cause infertility, and second cancers and lung issues can appear in some patients. About a third of pediatric survivors in this survey reported a severe, disabling or life-threatening chronic condition. The study showed the patients’ past cancer diagnosis can often shape their insurance and health care decisions later in life.

“Survivors have been through a lot when they were younger and understand the importance of making sure they can get health care when they need it,” explains Kirchhoff. “I think a lot of them also saw what their parents and families went through in terms of the financial stress and burden of dealing with a health crisis. So they’re just primed to understand the importance of health insurance.”

This study was conducted as the Affordable Care Act was rolling out. Kirchhoff says she would like to do a follow-up study to see if the insurance exchanges and Medicaid expansion have lessened job-related insurance worries. Kirchhoff also believes the study demonstrates what the country could expect if the ACA was dismantled.

The survey was funded by the National Institutes of Health/National Cancer Institute P30 CA042014 and U24 CA55727, the LIVESTRONG Foundation, and the Huntsman Cancer Foundation. Researchers from Massachusetts General Hospital and St. Jude Children’s Research Hospital also served as investigators on the study.

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