Key molecular regulator of uterine fibroids

Uterine leiomyomas, also called uterine fibroids, are benign tumors that originate from the smooth muscle of the uterus. Fibroids are the most common non-cancerous tumor of the female genital tract, affecting 80% of all women during their lifetime. More than half of women develop fibroids during their reproductive years, often complicating pregnancy. Fibroids are a major source of heavy uterine bleeding, pain, and reduced fertility, resulting in reduced quality of life and significant stress for many women. 

Treatments for fibroids consist of surgery, including hysterectomy or myomectomy, hormonal modulators, such as gonadotropin-releasing hormone agonists, and uterine arterial embolization (UAE), which blocks the blood supply to the tumor. The only true cure is surgical resection, with hormonal approaches and UAE estimated to shrink tumors by 30-40%. Bleeding and pain can also be significantly reduced by these treatments. However, results vary, and many women do not derive benefit from available procedures. Progress in designing new treatments has been slow, largely because we have a poor understanding of the biology of fibroids.

A new study recently identified a molecule that is expressed at abnormally high levels in fibroids. The molecule, H19, belongs to a class of molecules called long noncoding RNAs. H19 was found at increased levels in fibroid tissues from 30 women, including 20 premenopausal, compared with normal uterine myometrium tissues from the same women. High expression of H19 caused fibroid cells to double in number faster, whereas getting rid of H19 actually slowed down growth. Importantly, H19 also drove expression of molecular profiles that have previously been linked to fibroid development and growth. Thus, H19 may function upstream as a key regulator of fibroids. Estrogen and progesterone are thought to influence fibroid growth. This new study showed that combined exposure to estrogen and progesterone increased H19 expression and other fibroid-promoting genes. When H19 was eliminated, the effects of estrogen and progesterone were abolished. 

Although these results are preliminary, they are exciting for several reasons. We know so little about fibroids, and options for women who suffer from this debilitating chronic medical condition are limited. Fibroids receive little attention from the research community. The few studies that have been published in recent years are mostly preclinical in animal models and do not generally include patient samples. This new study used matched human fibroid and normal myometrium tissue from the same patients. This study also explored molecular mechanisms and biology, demonstrating cause and effect and not purely correlative findings.

Further studies are urgently needed to confirm the role of H19 and to identify other major mechanisms promoting fibroids. Identification of key regulators of fibroid development and growth moves us one step closer to understanding this disease and improving therapeutic options for women.

Reference: Cao T et al. Oncogene 2019 May 15

Simple health and wellness tips: screening and education

“No one is without knowledge except he who asks no questions.” ~ Ancient Proverb

You play an incredibly powerful role in dictating the course of your health. As discussed in the last post, 80% of chronic illnesses can be prevented through the lifestyle choices you make each day. But making informed decisions requires deliberate self-awareness and honesty. In addition to paying attention to diet and exercise, you can build self-awareness through active health screening and education. A major key to being proactive about your health is understanding your unique medical profile.

Know your body and your health risks. Routine medical, dental, and visual screenings help create a baseline profile of what’s normal for you. They may also help catch problems at early stages, when they are often easier to treat. Recommended evaluations may monitor blood pressure, cholesterol, glucose, body mass index, colorectal, breast, cervical, and/or prostate health (1). These tests are not just for primary prevention; they can help you follow ongoing concerns, so you can control progression of existing conditions. Staying up to date on immunizations, and practicing protective skin care are also important strategies for preventing serious medical problems. How frequently you decide to visit your doctor depends on your underlying health status and personal needs.

Medical visits should not be restricted to physician visits. Dental appointments are also important for your overall health. Gum disease, or periodontal disease, is diagnosed in more than 3 million people each year in the US (2). This bacterial infection is associated with poor dental care, resulting in swollen, red gums, loose teeth, and increased oral sensitivity. There is an increased risk of gum disease if you smoke or have diabetes, so dental care is especially important in these cases. Perhaps surprisingly, periodontal disease is not just an issue for your mouth. It increases your risk of developing serious systemic problems, including rheumatoid arthritis and heart disease (3). This occurs because the bacteria that cause gum disease can move through your blood, affecting blood vessels in the heart and creating harmful blood clots.

Outside of scheduled appointments, self-examination and an ongoing awareness of your physical and emotional wellness are critical. Recommended monthly self-exams include breast, testicular, and skin checks. Any sudden or persistent changes, such as lumps, pain, color, swelling, or rashes, can help identify problems early, increasing the probability of treating and curing an illness. As an example, if a woman feels a lump in her breast, she should act immediately and see a doctor. If a cancer is diagnosed and restricted to the breast, her chance of surviving 5 years is almost 99% based on statistics for women in the US (4). However, the 5-year survival from cancer that has spread from the breast to distant organs falls to 27%. These statistics vary patient to patient but emphasize the importance of early detection. Detecting the cancer before it spreads makes a significant difference in survival.

Despite the tremendous benefits of healthy lifestyle choices, our genetics are intimately tied to our risk profile of developing medical conditions. Therefore, to truly know your health risks, you must know your family history. It’s particularly important to keep a record of medical problems among first-degree relatives, meaning your parents, siblings, and children, since you share substantial genetic overlap. The National Institutes of Health actually recommends keeping a medical record for three generations of your family (5). The idea is to be aware of medical patterns in your family, including diseases for which you may have increased risk. It does not mean that you are going to develop the disease, but it does suggest that you should be proactive about taking steps to reduce your risk.

Understand your personal health record. A personal health record is a comprehensive set of your health information that you maintain and control. Everything about your health should be kept in this record. It may be a paper data set, electronic, or a combination. The information should be as complete as possible, including past and current illnesses, allergies, medications, health evaluations, surgeries, and family medical history. Ask your healthcare providers for records, such as images and reports, so you have them accessible when you want them. Having this record readily available is important for your peace of mind and that of your family. Simply creating the record is not enough; take steps to clearly understand everything in your record, including the side effect profiles of your medications, and how your medications interact with one another. Another advantage of having a personal health record is that you do not have to be dependent on your healthcare team for information. If you need information for work, travel, or a new doctor, you will have it available. If there’s an emergency, a family member can consult your record when contacting the hospital. Here is additional information to help you develop your personal health record.

Ask lots of questions, and know where to look for information. Our knowledge is only as deep as the quality and honesty of our questions. Ask openly about risk factors, prevention strategies, health and fitness, medications, and lifestyle changes. Even if your healthcare practitioner does not know the answer, he or she should be able to guide you to an appropriate source. If you feel that your questions are not being answered, or that you are being rushed, find a provider who will support your health enough to address your questions. If you have concerns about identifying credible written sources, ask your physician for advice. Scholarly databases, such as the National Library of Medicine, Medline Plus, and PubMed, are good places to start. Check out this site for great tips about credible sources of health information. When you read health articles online, pay attention to the affiliations, credentials and conflicts of interests of the website and author, as these may bias their advice. Medical research evolves rapidly, so check the date on your article to make sure you are reading the most recent information. It’s also useful to read articles with referenced sources, so you can go back and check the original articles. Checking multiple sites or articles for consistency of information, and consulting with your physician for advice are important steps towards ensuring that you can trust the information you are reading.

In our next post, we’ll cover simple strategies for integrating greater levels of balance and wellness into our lives.

Communicating research to a broader audience

Research is all about increasing knowledge. Everyone should have access to that education. Unfortunately, research findings often remain trapped for years in academic circles. Science graduate programs train students to speak to other scientists, with manuscripts and talks usually targeted to professional audiences. Although this is critical for driving research programs forward, it does not allow the general public to access new research information. One reason for the breakdown in communication from academic science to the public is the lack of training in effective public engagement. During the past decade, scientific writing and presentation courses have been added to graduate curricula. Equal attention should be paid to fostering communication outside of academic circles. Most science training programs do not include opportunities for public engagement. Only with practice can scientists actually learn how to convey their research in a meaningful, interesting, clear and concise manner that is relevant to a general audience.

In the absence of established activities, students can work with their advisors to seek out opportunities to write for public audiences. This could include sharing research through school newsletters, blog posts, or social media. Professors can also integrate lessons focused on speaking or writing for the public into existing courses and seminars. Simple assignments could include writing lay abstracts and general research summaries or presenting brief public seminars about a specific research project. Students can work with mentors to develop a 1-minute elevator pitch of their research to clearly articulate the intention or impact of their work. Remember that storytelling and analogies are highly effective ways to communicate complex information. Keeping the message simple with 1-3 main teaching points will reduce the chances of getting lost behind your words. Colleagues from writing and communications departments can be invited to review and critique students’ written summaries or public presentations. Outreach activities will also provide students with unique opportunities to speak at middle schools or community events, which will improve skills in public communication.

Bridging this gap in communication positively impacts academia and the public. Educating a wider audience imparts deeper meaning and purpose to the everyday work of scientists and graduate students. Most importantly, improved access to research findings empowers the public to advocate for their needs. As an example, patients should be privy to research news that may help clarify treatment decisions. Receiving a medical diagnosis is frightening and confusing, often because of the unknowns. Education is one of the biggest weapons we have to combat those fears, ask informed questions, and be proactive about our own healthcare. The academic community has a responsibility to disseminate research to the public in a timely manner. Science graduate programs should prioritize building skills in public communication and engagement to facilitate broader access to research advances and education.

Heading towards a better preclinical model of uterine leiomyoma

Uterine leiomyomas, which are also called uterine fibroids, are non-cancerous tumors arising from the smooth muscle of the uterine myometrium wall. The lifetime incidence of fibroids is estimated to exceed 70%, making these the most frequently diagnosed benign tumor of the female genital tract. Fibroids represent a major cause of heavy uterine bleeding, pain, and reduced fertility.

The biology of fibroid development is poorly understood, although its growth is largely thought to be estrogen-dependent. Currently, the only reliable curative medical option is hysterectomy. Other treatment options, such as uterine arterial embolization and hormonal therapy, can alleviate symptoms and reduce tumor size, but typically do not resolve the condition.

A major challenge with studying fibroids is the lack of physiologically relevant models in the lab. Evaluation of myoma tumor tissue ex vivo is complicated by eventual overgrowth of tumor-associated fibroblasts. Two recent papers published in Endocrine Related Cancer and Journal of Biological Methods report a method for developing patient-derived uterine leiomyoma xenografts (1,2). The investigators used tissue from the most common genetic subtype of uterine leiomyoma, the MED12-mutant subtype. After the tumor was surgically removed from the patient, the tissue was digested and cultured for 1-3 days. Cells were mixed with collagen and grafted into the subrenal capsule of ovariectomized mice. PDX uterine leiomyoma growth was documented in mice supplemented with both estrogen and progesterone. Removal of estrogen and progesterone resulted in a rapid reduction of tumor size of about 60%. Limitations of the model include differences in the hormonal and microenvironment of the kidney vs uterus.

Development of models that more closely mimic human uterine fibroids will allow us to gain increased knowledge about the biology and molecular mechanisms driving the development and growth of these tumors. These models may also be suitable for evaluating new treatment approaches for this common and debilitating condition.

(1) Serna VA, Wu X, Qiang W, Thomas J, Blumenfeld ML, Kurita T. Cellular kinetics of MED12-mutant uterine leiomyoma growth and regression in vivo. Endocr Relat Cancer. 2018 Jul;25(7):747-759.

(2) Serna VA, Kurita T. Patient-derived xenograft model for uterine leiomyoma by sub-renal capsule grafting. J Biol Methods. 2018;5(2).