Bad News for Smokers

June 12, 2015 by

By Medical Discovery News

June 5, 2015

Person smoking a cigarette

Smoking isn’t the only thing that raises your risk of lung cancer. As it turns out, your DNA can have that effect too.

A scientific study scanned the genomes, the entire genetic code, of 11,000 people of European descent in an effort to identify if there was any correlation between gene sequences and a common form of lung cancer, non-small cell carcinoma. They discovered that variants of certain genes increase a person’s susceptibility to developing lung cancer, especially in smokers.

One of the three gene variants they identified, named BRCA2, can double a smoker’s chance for developing lung cancer. BRCA2 is a tumor suppressor gene. It encodes a protein involved in the repair of damaged DNA, which is critical to ensure the stability of cell’s genetic material. When cellular DNA is damaged, there are several ways for the body to detect and repair that damage. If the damage to DNA cannot be repaired, then the cell is programmed to die by a process called apoptosis in order to prevent the damage being passed on to its daughter cells.

Like other tumor suppressor genes, the BRCA2 protein helps to repair breaks in DNA. It also prevents damaged cells from growing and dividing too rapidly. Variants of BRCA2 associated with breast, ovarian, and now lung cancers produce proteins that do not repair DNA damage properly. This causes cells to accumulate additional mutations, which can lead to cells that grow and divide uncontrollably. Such mutations lead to an increased risk of developing cancer.

Scientists have discovered over 800 mutations of BRCA2 that cause disease, including breast, ovarian, lung, prostate, pancreatic, fallopian, and melanoma cancers. Most of the mutations result from the insertion or deletion of a few letters of genetic code into the part of the gene that code for a protein. This disrupts the production of the BRCA2 protein and results in a shortened and nonfunctional form of the BRCA2 protein.

Lung cancer is a leading killer of Americans. Nearly 160,000 Americans will die from lung cancer this year, representing 27 percent of all cancer deaths. Active smoking causes close to 90 percent of lung cancers.

The good news from this discovery is that since scientists first linked BRCA2 to an increased risk of breast cancer, new therapies have been developed. Current treatments for breast and ovarian cancers could be effective with BRCA2-associated lung cancers, such as PARP inhibition.  PARP1 is another protein involved in repairing DNA damage. When one of two strands of DNA are broken or nicked, PARP1 moves to the region and recruits other proteins to the site to repair the damage. Many chemotherapy agents kill cancer cells by inducing DNA damage in the tumor and inhibiting PARP1. This doesn’t allow cancer cells to repair damage and makes them more susceptible to chemotherapy and radiation therapy. Now that we know this gene is linked to lung cancer, such therapies may be more effective in treating lung cancer and saving lives.

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A Close-Up Look at Metastasis

June 12, 2015 by

By Medical Discovery News

May 29, 2015

A Close-Up Look at Metastasis

One of the things that make cancer cells so deadly is metastasis, their ability to dislodge from their original location and migrate to other tissues. Most people who die of cancer are victims of this process. Even if a tumor is removed surgically, doctors can’t be certain that some of the tumor cells haven’t already metastasized, hence the need for treatments such as chemotherapy to target those cells. Unsurprisingly, metastasis is a subject of intense research, and luckily scientists now have a new tool to help them understand how tumor cells move.

While most tumors have the ability to metastasize to many different tissues, they prefer to spread to certain ones, like those in the bones, liver, and lungs. Cancer begins to spread by invading nearby tissue, then through a process called intravasation, tumor cells enter a blood or lymphatic vessel, allowing them to circulate to other parts of the body.

When tumor cells stop moving in a tiny blood vessel called a capillary, the can move out of the blood vessel and into the tissue, which is called extravasation. They will proliferate in this new location and release signals to stimulate the production of new blood vessels to satisfy the oxygen and nutrient demands of the tumor, a process called angiogenesis. Not all cells of the tumor are equally capable of metastasizing, and depending on the new environment they may not be able to grow in their new locations. In general, cells in metastatic tumors acquire additional genetic mutations that make them better able to relocate to other sites in the body. In some cancers, the metastatic cells have evolved to be remarkably different from the original tumor cells, which may contribute to the failure of treatments, the identity of the original cancer, and the recurrence of cancer.

Engineers and scientists at Johns Hopkins University have reproduced the 3-D extracellular matrix (ECM) that surrounds human cells. They also created an artificial blood vessel that runs through the matrix to simulate the flow of blood or lymph. They then added breast cancer cells either individually or in clumps.

Using fluorescent microscopy, they studied how the tumor cells interacted with the model to investigate how tumor cells get into and out of vessels, a key step in metastasis. They found that the tumor cells first dissolved some of the ECM to form a tunnel. The cells moved back and forth within this tunnel, occasionally coming into contact with the vessel. Then the cancer cells attached to the vessel through a long process, finally sitting on the surface of the blood vessel. They appear to change shape and move along the outer surface of the blood vessel. After a few days, the cancer cells force their way between the outer cells of the vessel and are swept away by the fluid moving through it.

About 60-70 percent of cancer patients are already at the stage of metastasis by the time they have been diagnosed. This new device will allow scientists to gain a better understanding of the processes and molecular players in metastasis, which will hopefully lead to new interventions or therapies that could interrupt or prevent this process.

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The Berlin Patient

February 22, 2015 by

Feb. 27, 2015

By Medical Discovery News

Millions of people around the world are infected with HIV, the virus that causes AIDS, but only one has ever been cured. Known as the “Berlin Patient,” Timothy Ray Brown is a 48-year-old American living in Germany. Scientists and physicians have wondered how he was cured, and some recently published studies in monkeys have provided one clue.

Brown had been HIV positive since 1995. When HIV infects the body’s cells, it integrates its genetic information into cells, making the virus a permanent part of the host’s genetic information. Brown’s HIV was held at bay by antiretroviral drugs that have made this infection survivable.  However, in 2006 he was diagnosed with acute myeloid leukemia (AML), a cancer unrelated to HIV. AML affects a group of blood cells in bone marrow called the myeloid cells. Brown underwent grueling chemotherapy that failed. In the hope of saving his life, he received two bone marrow transplants. The year of his first transplant, he stopped taking the antiretrovirals, which would normally cause a patient’s HIV levels to skyrocket.

Yet, years later, there is no sign of the virus returning. Only traces of HIV’s genetic material have been found in his blood, and those pieces are unable to replicate. The big question now is: how was this accomplished?

His treatment for AML included three different factors that could have individually or collaboratively resulted in curing his HIV infection. First, in preparation for a bone marrow transplant, a patient is treated with a combination of chemotherapy and whole body radiation to eliminate the entire immune system in preparation for receiving a new one. Second, Brown received blood stem cell transplants from a person with a defective cell surface protein, CCR5, which is what HIV uses to enter cells. People with a CCR5 mutation are resistant to HIV infection. Third, his new immune system may have eliminated the virus and remnants of his old immune system that harbored it in something called a graft versus host reaction.

In an experiment to determine how Brown was cured of HIV, scientists isolated blood stem cells from three Rhesus Macaque monkeys and put them into cold storage. They then infected those monkeys as well as three control monkeys with an engineered version of HIV. Soon after infection, all six monkeys were treated with a cocktail of drugs, and just like in humans, the levels of the virus soon declined. A few months later, the first three monkeys underwent radiation treatments to eliminate their immune systems, and then their immune systems were restored using their own stem cells from storage. Months later, the antiretroviral drugs were withheld from all six monkeys, and the virus came roaring back in five of them. One of the monkeys who underwent the stem cell transplant did not have the virus return in its blood, but it was detected in some tissues.

This experiment established that the destruction of immune system prior to bone marrow transplant was not sufficient to eliminate the virus, so the selection of bone marrow cells resistant to HIV infection and/or the graft versus host reaction may be the reason Brown was cured of HIV. Further studies are needed before we will know exactly how HIV can be cured.

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