Mouse Model Discovers Two Genes Behind The Most Severe Form Of Ovarian Cancer

Dr. Enrique Jacome

In a new study reported in the journal Nature Communications, cancer researchers describe how they developed a mouse model of a very aggressive ovarian cancer that accurately portrays the disease as it occurs in humans. The model has helped them identify two mutated genes whose interaction appears to trigger, then hasten, the development of the cancer.

The researchers, from the University of North Carolina (UNC) at Chapel Hill, hope their findings will open new avenues to better treatments and much-needed diagnostic screens.

Ovarian cancer affects the ovaries, the reproductive organs responsible for producing eggs and female hormones in women.

Ovarian cancer is hard to detect, because the symptoms - such as feeling bloated and experiencing changes in appetite - are often mistaken for other conditions. There is also no effective diagnostic screen for early detection of ovarian cancer.

When ovarian cancer is found early, it can be highly treatable, and the 5-year survival rate in such cases is over 90%. But unfortunately, only 1 in 5 cases are found early, leaving the majority of patients to learn that their cancer has spread, is at an advanced stage that is hard to treat and their prognosis is stark.

While the pace is slow, the situation is gradually improving. Thirty years ago, the survival rate for women diagnosed with ovarian cancer in the US was 10-20%. Nowadays, it is nearer 50%. 

According to the American Cancer Society (ACS), a woman's risk of getting ovarian cancer during her lifetime is about 1 in 75, and her lifetime chance of dying from the disease is about 1 in 100.

The ACS estimate that in 2015, about 21,290 women in the US will receive a new diagnosis of ovarian cancer and about 14,180 women will die from the disease.

New mouse model depicts aggressive ovarian cancer just as it presents in humans

The senior author of the new study is Terry Magnuson, the Sarah Graham Kenan Professor and chair of UNC's Department of Genetics. He says the new model portrays an extremely aggressive form of ovarian cancer - ovarian clear cell carcinoma - just as it presents in women.

Not all mouse models of human conditions are able to portray them as accurately as they occur in humans. But the model that Prof. Magnuson and colleagues have developed is based on genetic mutations found in human cancer samples.

Prof. Magnuson says they used the mouse model to show how mutations in two genes - ARID1A and PIK3CA - interacted to trigger the aggressive ovarian cancer:

"When ARID1A is less active than normal and PIK3CA is overactive, the result is ovarian clear cell carcinoma 100% of the time in our model."

The team was also able to use the mouse model to show that BKM120, a drug that suppresses PI3 kinases - proteins that are involved in cancer cell growth, survival and proliferation - directly inhibited ovarian tumor growth and significantly prolonged the lives of mice.

BKM120 is currently undergoing human trials for the treatment of other cancers.

Two gene mutations interact to trigger aggressive ovarian tumor formation and growth

The study arose from previous work that found the ARID1A gene was highly mutated in several types of tumor, including ovarian clear cell carcinoma. But that work also found deleting the gene in mice did not trigger tumor formation or growth.

This is how the UNC team found the gene needed to interact with another gene, as Dr. Ronald Chandler, a postdoctoral fellow in Prof. Magnuson's lab, explains:

"We found that the mice needed an additional mutation in the PIK3CA gene, which acts like a catalyst of a cellular pathway important for cell growth. Too little expression of ARID1A and too much expression of PIK3CA is the perfect storm; the mice always get ovarian clear cell carcinoma. This pair of genes is really important for tumorigenesis."

Dr. Chandler says their research also "shows why we see mutations of both ARID1A and PIK3CA in various cancers, such as endometrial and gastric cancers."

The team also discovered that ARID1A and PIC3CA mutations were involved in overproduction of a protein that helps trigger inflammation. They say they do not know if inflammation causes ovarian clear cell carcinoma, but they do know it is important for tumor cell growth.

Speaking about the protein - Interleukin-6, or IL-6 - Prof. Magnuson says: "We think that IL-6 contributes to ovarian clear cell carcinoma and could lead to death. You really don't want this cytokine circulating in your body."

He suggests when they treated tumor cells with an antibody that targets IL-6, it inhibited cancer cell growth, so perhaps reducing levels of IL-6 could help patients, he adds.

The potential for new ways to diagnose ovarian cancer

The researchers say that while their work will help identify better treatment targets, it may also lead to new ways of diagnosing ovarian cancer.

Dr. Chandler says maybe they could find a biomarker that could be used to screen women. Perhaps there is a cell surface protein "downstream of ARID1A," he suggests, adding that:

"Right now, by the time women find out they have ovarian clear cell carcinoma, it's usually too late. If we can find it earlier, we'll have much better luck successfully treating patients."

The study was funded by the National Institutes of Health, with additional support from the ACS and the Ovarian Cancer Research Fund.

In March 2014, Medical News Today learned how scientists achieved another breakthrough by finding the genetic cause of a rare, aggressive ovarian cancer that most often strikes girls and young women. 

In that study - which used groundbreaking genomic techniques - the international team found several strong links between a mutation in the SMARCA4 gene and a large majority of patients with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).

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The Health Benefits Of Iron

Dr. Enrique Jacome

Iron deficiency anemia is the world's most common nutritional deficiency disease and is most prevalent among children and women of childbearing age. Anemia develops due to an inadequate amount of iron in the diet or poor iron absorption.

Iron deficiencies can be caused or exacerbated by injury, blood loss, hemorrhage or gastrointestinal diseases that impair iron absorption. Inadequate intake of folate, protein and vitamin C can also contribute to iron deficiency.

MNT Knowledge Center feature is part of a collection of articles on the health benefits of popular vitamins and minerals. It provides an in-depth look at recommended intake of iron, its possible health benefits, foods high in iron and any potential health risks of consuming iron. 

Recommended intake

The Recommended Daily Allowance (RDA) for iron depends on age and gender. 

Children:

• 1-3 years - 7 milligrams 
• 4-8 years - 10 milligrams.

Males:

• 9-13 years - 8 milligrams
• 14-18 years - 11 milligrams
• 19 years and older - 8 milligrams.

Females:

• 9-13 years - 8 milligrams
• 14-18 years - 15 milligrams
• 19-50 years - 18 milligrams
• 51 years and older - 8 milligrams.

Pregnancy:

• 27 milligrams.

An estimated 8 million women of childbearing age in the US suffer from iron deficiency severe enough to cause anemia. Iron deficiency during pregnancy may raise the risk for preterm delivery.

Iron supplements are available, but it is best to obtain any vitamin or mineral through food first. It is not the individual vitamin or mineral alone that make certain foods an important part of our diet, but the synergy of the foods nutrients working together. It has been proven time and again that isolating certain nutrients in supplement form will not provide the same health benefits as consuming the nutrient from a whole food. First focus on obtaining your daily iron requirement from foods then use supplements as a backup.

Possible health benefits of consuming iron

Iron deficiency can cause many health problems. Common difficulties associated include delayed cognitive function, poor exercise performance and lowered immune function. In children, iron deficiency anemia can cause psychomotor and cognitive abnormalities resulting in future learning difficulties.

Healthy pregnancy

Low iron intakes increase a woman's risk of premature birth and the risk of her infant having low birth weight, low iron stores and impaired cognitive or behavioral development.

More energy

Not getting enough iron in your diet can affect how efficiently your body uses energy. Iron carries oxygen to the muscles and brain and is crucial for both mental and physical performance. Low iron levels may result in a lack of focus, and an increase in irritability. 

Better athletic performance

Iron deficiency is more common among athletes, especially young female athletes, than sedentary individuals. Iron deficiency in athletes decreases athletic performance and weakens immune systems. A lack in hemoglobin iron can greatly reduce physical work performance via a decrease in oxygen transport to exercising muscle. 

Foods high in iron

Iron has a low bioavailability, meaning that it has poor absorption within the small intestine and low retention in the body, decreasing its availability for use. The efficiency of absorption depends on the source of iron, foods consumed with the iron, and overall iron status of the person. In many countries, wheat products and infant formulas are fortified with iron.

There are two types of dietary iron - heme and non-heme. Most animal products and seafood contain heme iron, which is easier to absorb than non-heme. Non-heme iron sources include beans, nuts, vegetables and fortified grains. The recommended iron intake for vegetarians is 1.8 times higher than for those who eat meat in order to make up for the lower absorption level from plant-based foods.

Proton pump inhibitors (lansoprazole [Prevacid®] and omeprazole [Prilosec®]) used to reduce the acidity of stomach contents can inhibit the absorption of iron. The polyphenols and tannins in coffee and tea also decrease non-heme iron absorption. Eating foods that are high in vitamin C, on the other hand, help to increase iron absorption.

Clams contain a significant 24 mg of iron per 3 oz.

• Clams, canned, 3 oz: 24 milligrams
• Cereal, fortified, one serving: 1-22 milligrams
• White beans, canned, 1 cup: 8 milligrams
• Chocolate, dark, 45-69% cacao, 3 oz: 7 milligrams
• Oysters, cooked, 3 oz: 6 milligrams
• Spinach, cooked, 1 cup: 6 milligrams
• Beef liver, 3 oz: 5 milligrams
• Blueberries, frozen, ½ cup: 5 milligrams
• Lentils, boiled and drained, ½ cup: 3 milligrams
• Tofu, firm, ½ cup: 3 milligrams
• Chickpeas, boiled and drained, ½ cup: 2 milligrams
• Tomatoes, canned, stewed, ½ cup: 2 milligrams
• Ground beef, lean, 3 oz: 2 milligrams
• Potato, baked, medium: 2 milligrams
• Cashew nuts, roasted, 1 oz: 2 milligrams
• Egg, 1 large: 1 milligram.^1,2

Potential health risks of consuming iron

The tolerable upper intake level for iron is between 40-45 milligrams. Adults with healthy functioning gastrointestinal systems have a very low risk of iron overload from dietary sources. 

Taking iron supplements of 20 milligrams or more on a frequent basis can cause nausea, vomiting and stomach pain, especially if the supplement is not taken with food. In severe cases, iron overdoses can lead to organ failure, coma, seizure, and even death.

Some studies have suggested that excessive iron intake can increase the risk of coronary heart disease and cancer.

Iron supplements can interact with several medications, including levodopa (used to treat restless leg syndrome and Parkinson's) and levothyroxine (used to treat hypothyroidism, goiter, and thyroid cancer). 

It is the total diet or overall eating pattern that is most important in disease prevention and achieving good health. It is better to eat a diet with a variety than to concentrate on individual nutrients as the key to good health.

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