Cancer cells ability to break free and spread arises from broken switch

A report on the discovery by the Institute of Cancer Research (ICR) in London, United Kingdom - is published in the journal Cell Systems.Study leader Dr. Chris Bakal, who heads the dynamical cell systems team in ICR's Division of Cancer Biology, says that their investigation shows how invasive cancer cells have acquired the ability to overcome the normal constraints on cell movement.

The vast majority of cancer deaths occur because the cancer spreads from the primary tumor to other parts of the body.This process of cancer spread is called metastasis, and it arises because cancer cells acquire the ability to migrate. Finding ways to prevent or halt metastasis could save many lives.

Researchers have already discovered many physical and chemical differences between metastatic and non-metastatic cells.In 2013, for example, a large group of scientists published a catalog describing the mechanical properties of metastatic cells, how they stick to surfaces, migrate, respond to oxygen, and produce protein.

However, what has not been so clear is what happens at the molecular level to disrupt signaling that changes the character of the cell and its relationship to its environment.'Broken switch' allows continual YAP production. In the new study, the ICR team describes how it found that cancer cells that spread around the body have a broken switch that continually activates an important molecule called YAP.

YAP acts as a "mechano-sensor" that allows the cell to "feel" its surroundings - such as how it adheres to the extracellular matrix. The extracellular matrix is a non-cellular component comprising water, proteins, and other molecules secreted by cells that hold them place and regulate key biochemical and biomechanical signals.Normally, a cell's ability to grasp onto and move around tissues in the body is tightly constrained by its relationship to the extracellular matrix and other cells. However, YAP can overcome these physical constraints by switching on genes that are usually turned off.

The team found that unlike normal cells - where YAP production and activity are carefully regulated - cancer cells that are able to spread produce YAP all the time, allowing them to escape their physical constraints.The researchers found that a molecule called beta-PIX partially controls YAP signaling. They discovered it by systematically switching off 950 genes one by one in laboratory-grown cancer cells.

In further experiments, the team discovered that beta-PIX boosts YAP activity as the cell adheres to the extracellular matrix while moving through tissue.When cells were forced to remain stuck to the matrix, YAP activity was even higher. However, it greatly reduced when levels of beta-PIX molecules depleted. The researchers then looked more closely at how the link between beta-PIX and YAP behaves in metastasis. They examined it in triple-negative breast cancer cells from primary tumors and in cells from secondary tumors.

As expected, tests showed that disabling the beta-PIX pathway in cancer cells from primary tumors failed to activate YAP. However, doing the same to metastatic cells in secondary tumors did activate YAP.The researchers suggest this shows that the link between beta-PIX and YAP is broken in metastatic cells, thereby allowing them to maintain high levels of YAP even when not bound to the extracellular matrix.

Source: http://www.medicalnewstoday.com/articles/315071.php

Existing drug could prevent spread of triple-negative breast cancer

New research has revealed that breast cancer metastasis may be prevented by a class of drugs that have already been approved in the US.Metastasis is the process by which cancer spreads. Researchers at the US’ Mayo Clinic have identified that enzyme pathway CDK4/6 regulates a cancer metastasis protein, known as Snail. They found that drugs that inhibit CDK 4/6 could also prevent the spread of triple-negative breast cancer.

Currently, CDK4/6 inhibitors are approved for treating estrogen-positive breast cancer, but not triple-negative breast cancer.Study senior author Dr Zhenkun Lou, of the Mayo Clinic, explained: “Metastasis is a hallmark of cancer and a leading cause of cancer death. Despite great progress in cancer therapy, the prevention of cancer metastasis is still an unfulfilled challenge.”

During this study, the researchers focused on triple-negative breast cancer. This is a very difficult to treat cancer because it does not exhibit receptors for estrogen, progesterone or the HER-2/neu gene, which are targets for many current breast cancer treatments.Dr Lou said: “Prior published data suggested that CDK 4/6 inhibitors were not effective in reducing the growth rates of estrogen receptor-negative breast cancer.

“Our data confirmed that, while the rate of growth of triple-negative breast cancer was not affected by CDK 4/6 inhibitors, this class of drugs was able to significantly inhibit the spread of triple-negative breast cancer to distant organs when tested in multiple different triple-negative breast cancer models, including patient-derived xenografts.”

Patient-derived xenographts involve the implantation of tumour tissue into an immunodeficient mouse which becomes an avatar to help identify which drug or drug combinations are most likely to be effective for an individual cancer patient.

Source: http://www.figo.org/news/existing-drug-could-prevent-spread-triple-negative-breast-cancer-0015456

Delayed chemotherapy after surgery may still be beneficial

Lung cancer is by far the most common cause of death from cancer worldwide, accounting for almost 1 in 5 cancer deaths (1.59 million out of 8.2 million in 2012).AA new study published in JAMA Oncology suggests that patients with a common form of lung cancer who need time to recover from surgery may still benefit from delayed chemotherapy.

In the United States, the chances of developing lung cancer over a lifetime are about 1 in 14 for men and around 1 in 17 for women. The chances are much higher for people who smoke and lower for people who do not.While the prognosis, or outlook, for patients diagnosed with lung cancer is usually poor, if the disease is diagnosed in the early stages, there is a higher chance of a cure.More than 430,000 people in the U.S. alive today have been diagnosed with lung cancer at some point in their lives.

There are two main types of lung cancer. Approximately 80-85 percent of lung cancers are non-small cell lung cancer (NSCLC), and around 10-15 percent are small cell lung cancer. These types are treated very differently.The new study - from Yale University in New Haven, CT - concerns NSCLC, of which there are two subtypes that each arise from a different type of lung cell. However, they are usually grouped together because the approaches to their treatment and prognosis are often similar.

Patients with NSCLC who undergo surgery to remove the tumor may receive chemotherapy afterward to reduce the risk of the cancer returning.In their paper, the Yale researchers note the standard recommendation is that chemotherapy should be administered for NSCLC patients whose cancer has spread to the lymph nodes, whose tumors are 4 centimeters or larger, or where there is extensive invasion into surrounding tissue.

However, while there is general consensus regarding such use of chemotherapy - called adjuvant chemotherapy because it is additional to the main treatment - the optimum timing is not clear.Many doctors say that the optimum window for giving adjuvant chemotherapy to NSCLC patients is 6-9 weeks following surgery.

However, there are cases where patients need to recover from complications following surgery, and they may not be able to tolerate chemotherapy so soon.For their study, Daniel J. Boffa, associate professor of surgery at Yale School of Medicine, and colleagues analyzed data on patients in the National Cancer Database in order to examine the relationship between timing of chemotherapy after surgery and 5-year survival.

The National Cancer Database is a hospital-based tumor registry, capable of capturing over 70 percent of U.S. incident lung cancer cases.Chemotherapy after traditional window may still benefit
The analysis included 12,473 NSCLC patients who met the standard recommendation for adjuvant treatment and received chemotherapy between 18 and 127 days after surgery during 2004-2012.

Results showed that 5-year survival for patients whose chemotherapy started 7-18 weeks following surgery differed little from patients whose chemotherapy started closer to the 6-9-week window that is generally followed.The analysis also found that surgery followed by delayed chemotherapy was associated with a lower risk of death compared with surgery only.

Researchers conclude that while they did not look at the underlying causes, the results suggest that delaying chemotherapy outside the traditional postoperative window may still offer benefit to NSCLC patients.

Source: http://www.medicalnewstoday.com/articles/315103.php