Treating aggressive colon tumor with immunotherapy

Immunotherapy against cancer cells has become a powerful approach to treat cancers such as melanoma and lung cancer. However, to date, most colon tumours appeared to be unresponsive to this kind of therapy. Given this observation, researchers hypothesized that this kind of tumour was simply invisible to the immune system.

A team headed by ICREA researcher Eduard Batlle, at the Institute for Research in Biomedicine (IRB Barcelona), explains that the hormone TGF-beta is responsible for the "blindness" of the immune system to colon cancer cells. The few clinical immunotherapy trials done in patients with the most common subtype of colon cancer were not giving good results.

By inhibiting the activity of TGF-beta, the cells of the immune system infiltrate and recognise the tumour, fight the cancer, and even stop colon tumours from metastasizing to the liver and lung in a preclinical mouse model that mimics the human disease. In addition, and more importantly, the researchers demonstrated that the combination of a TGF-beta inhibitor with available immunotherapies boost the anti-tumour effect, allowing the immune system to efficiently eliminate already established metastases that would otherwise kill the individual in a question of weeks.

Scientist Daniele Tauriello, postdoctoral fellow and first author of the article, induced four of the most common mutations present in advanced human colon tumours in mice. After confirming the similarity of the mouse tumours with those in humans, they built a biobank of tumour organoids3-D mini-tumours and grafted them in a controlled manner in immunocompetent mice.

For studies of the immune system, the tumour has to be of mouse origin. Otherwise, the animal would reject it.This animal model which mimics the main features of metastatic colon cancer in humans, allowed the researchers to examine how cancer cells evade the immune system. Around 40 to 50 percent of colon cancer patients relapse in the form of metastasis, with the tumours reproducing mainly in the liver and lung.

Once advanced stage colon cancer is diagnosed, oncologists do not have access to efficient treatments to cure the patient. This study paves the way for the development of the first immunotherapy treatment for patients with metastatic colon cancer and for those patients with poor prognosis but who have not yet developed metastasis. Oncologists and pharmaceutical companies will soon start clinical assays that combine TGF-beta inhibitors, which are already in clinical use, with immunotherapies.

The researchers are convinced that many colon cancer patients will benefit from this therapeutic strategy. In the same issue of Nature, another study addresses the lack of response of bladder cancer patients to immunotherapy.  It appears that many types of tumour use the same strategy-increasing the expression of TGF-beta in the environment to evade the immune system. Patients with these tumours may also benefit from immunotherapies based on the inhibition of this hormone.
          haleplushearty.blogspot.com

Small molecule reduce the spread of cancer

One small molecule that regulate gene expression plays a big role in keeping human safe from the machinations of cancer. In human lung cancer cells, low levels of the microRNA, miR-125a-5p, which enables the death of aberrant cells like cancer cells, correlates with high levels of the protein TIMP-1, which is already associated with a poor prognosis in patients with cancer.

Conversely, when they decrease TIMP-1 levels in these highly lethal cancer cells, tumor spread goes down while rates of cell death go up along with expression of miR-125a-5p, says Dr. Mumtaz V. Rojiani, cancer biologist in the Department of Medicine at the Medical College of Georgia and a member of the Molecular Oncology and Biomarkers Program at the Georgia Cancer Center at Augusta University.

While increasing microRNA levels is technically difficult, further delineating how cancer hijacks these normal body systems may help identify new treatment targets. TIMP-1 has a positive role in a healthy body to balance levels of enzymes the body makes to ease cell movement for things like wound healing or reproduction.

The healthy body and cancer make these enzymes, matrix metalloproteinases, or MMPs, to break down the surrounding matrix that helps keep cells stable. While it's critical to positives like wound healing, when the matrix breakdown is usurped by cancer, it also gives cancer cells this freedom to move.

In cancer, TIMP-1 levels rise dramatically and it has a distinctive role enabling both growth of new blood vessels and inhibition of apoptosis, a cell's natural inclination to die if something unfixable is wrong. In cancer, what the tumor cells do is start secreting a lot more of these enzymes so they can break down the matrix and start migrating and metastasizing.

Classically, TIMP-1 should be inhibiting MMPs but over the years it has been found to have other functions that actually increase tumor aggressiveness. In their studies of TIMP-1 expression in human lung cancer cells, they saw this aggressive response. It turned out that TIMP-1 is like a two-faced individual smiling at cancer sometimes and other times cutting it off.

Increased levels of two-faced TIMP-1 have been found in increased tumor spread and poor prognosis in breast, gastric and colorectal cancers as well as the non-small cell lung cancer the MCG scientists studied, which accounts for about 85 percent of all lung cancers and has a five-year survival rate of under 20 percent.

TIMP-1 overexpression also is associated with increased upregulation of Bcl-2, a protein which can prevent apoptosis, or cell death. To make bad matters worse, a key way chemotherapy works is by inducing apoptosis and TIMP-1 has been associated with potentially deadly drug resistance.
However, with high expression of miR-125a-5p, TIMP-1 becomes the target. One result is increased expression of the gene p53, a known tumor suppressor, which enables cell death.

When ressearchers knocked down TIMP-1 expression, it significantly increased expression of miR-125a-5p. Conversely, when they restored higher levels of TIMP-1, miR-125a-5p expression went down. The look of the cancer cells changed with the level of TIMP-1. At high levels they looked more like cells unshackled from their current location and able to migrate and invade. When they decreased TIMP-1 levels, the cells pretty much stayed put.

 Adding more synthetic miR-125a-5p to the cancer cells, and the lung cancer cells moved more toward a stationary normal look and cell death increased. When they inhibited miR-125a-5p, the cells were ready to roam. Looking at the biopsies of lung cancer patients, they found as expected TIMP-1 expression much higher in the lung cancer tissue than nearby healthy tissue. But they also saw an inverse relationship between high levels of TIMP-1 and miR-125a-5p levels. In fact, tumor cells had almost no miR-125a-5p.
             haleplushearty.blogspot.com

Lung cancer causes hypertension

Shortness of breath and respiratory distress often increase the suffering of advanced-stage lung cancer patients. These symptoms can be triggered by pulmonary hypertension, the pulmonary hypertension is due to immune and inflammatory processes triggered by cancer cells. Lung cancer has long since taken on the character of an epidemic: the disease is already responsible for more than a quarter of all cancer deaths, and the trend is rising.

One reason for this is that the prognosis is poor: only one-fifth of patients are still alive five years after diagnosis. This is partly due to the fact that lung cancer is often not recognized until it is in an advanced stage. Another problem is that a variety of different lung cancers exist, each of which requires its own therapeutic concept. Doctors have observed that many patients with progressive lung cancer develop shortness of breath and respiratory distress.

The same symptoms also occur in diseases such as pulmonary arterial hypertension. Scientists measured the diameter of the pulmonary artery of many lung cancer patients using computer tomography. They found thickening of the walls of the pulmonary artery in more than half of the patients. This is a clear indication that these patients also suffer from pulmonary hypertension.

To identify the causes, the lung researchers analyzed three different forms of lung cancer in mice. These were tumour types that grow at different rates and can be experimentally induced in the lungs of mice. All three mouse models showed signs of pulmonary hypertension as tumour growth progressed.

Further experiments showed that the immune cells release various chemical messengers, as is generally observed in inflammatory reactions. Conversely, pulmonary hypertension did not occur when the mice in the experiment lacked functioning immune cells. This is an indication that inflammatory processes triggered by lung cancer may be responsible for pulmonary hypertension.
          haleplushearty.blogspot.com

Lung cancer genetic biomarkers

Single-nucleotide polymorphisms SNPs are variations in human DNA that determine human susceptibility to developing some diseases. Using the largest genome-wide SNP-smoking interaction analysis reported for lung cancer, researchers identified three novel SNPs. The results from their study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and responsible for part of the missing heritability of this disease.

Environmental and genetic risk factors contribute to development of lung cancer. Tobacco smoking is the most well-known environmental risk factor associated with lung cancer. They conducted a study to display that gene-smoking interactions play important roles in the etiology of lung cancer.

In their study, three novel SNPs (single-nucleotide polymorphisms), or variations in our DNA that underlie human susceptibility to developing disease, were identified in the interaction analysis, including two SNPs for non-small cell lung cancer risk and one SNP for squamous cell lung cancer risk. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention.

The genotype and phenotype data used in this analysis came from OncoArray Consortium. Genome-wide interaction scanning remains a challenge as most genome-wide association studies are designed for main effect association analysis and have limited power for interaction analysis.

The three SNPs, identified in the team's study, stratify lung cancer risk by smoking behavior. These three SNPs can be potential biomarkers used to improve the precision to which researchers can categorize an individual's risk of lung cancer disease by smoking behavior, which are helpful for individualized prognosis and prediction of treatment plan.
          haleplushearty.blogspot.com

Lung cancer treatment could affect the heart

Radioactivity of the heart from
radiotherapy of lung cancer treatment is increasing mortality rates. Exposing heart to radiation during treatment of lung cancer may kill the organ.

Some tumours are very close to the heart, higher dose of radiotherapy to this part of the body increases the risk of early death. During radiotherapy, some radiation will hit the heart because it is very close to the lung and this have negative effects on it

Researchers analysed many patients, looking at where in the heart there was radiation and how long the patients survived. They identified that the top of the heart is very sensitive to radiation than the body of the organ.

The researchers carried out a high-resolution, normal-tissue dosimetric analysis, this identify regions in the heart that correlated with poorer survival. The result confirmed that radiation affects the heart.
          haleplushearty.blogspot.com

HIV positive smokers may die of lungs cancer

HIV patients who smoke cigarettes are more likely to die from lung cancer than from HIV, antiviral drugs increased the life span of HIV patients
but there is no drug for preventing lung cancer that is as effective as antiretroviral therapy ART for HIV.

According to researchers, lung cancer prevention through smoking cessation should be a priority in taking care of people living with HIV. Researchers examined people with HIV who were current, former and never smokers.

They discovered that people who consistently take their anti-HIV medications but continue to smoke will die of lung cancer. Lung cancer is one of the leading killers of people with HIV, smoking and HIV put them at risk of developing lung cancer at a rate higher than smokers not infected with HIV.

Smoking and HIV are bad combination when it comes to lung cancer. Smoking cessation is one of the most important things that people living with HIV can do to improve their health and live longer. It will reduce their risk of lung cancer, heart attack, stroke, and emphysema.
          haleplushearty.blogspot.com

Vitamin B increases the risk of lungs cancer

According to a new study, high-dose and long-term use of vitamins B12, B6 and smoking increase the risk of lung cancer. Using high dose of vitamin B6 and B12 may leads to development of lungs cancer.

Researchers analyzed data from some patients and evaluate vitamin and other mineral supplements in relation to cancer risk. They discovered that men who take high-dose of vitamin B6 and B12 supplements for a decade had higher risks for developing lung cancer.

Human body needs vitamins B6 and B12 to ensure red blood cells are healthy and to process proteins, fat and carbohydrate. Foods rich in vitamin B are: meat, fish, cheese, eggs and milk, and fortified cereals.

 Some vitamin B supplements contained doses which were higher than the daily recommended amount, eating foods rich in vitamin B is enough for vitamins required. The discovery shows that taking high doses of B6 and B12 for a long period of time could increase the risk of developing lung cancer.
          haleplushearty.blogspot.com

Reasons for deadly resistance in lung cancer and melanoma

Researchers have discovered why some lung cancer and melanoma develop deadly resistance to targeted therapies.
 Intricate DNA sequencing tests was performed on single cells using genetic models of lung cancer and melanoma.

Lung cancer and melanoma are amongst the hardest to treat of all the cancers because of their capacity to change their genetics and developing resistance to targeted therapies.

 Researchers used animal models from tumours derived from patients and single-cell genomics to develop a hypothetical model of resistance, known as "fitness threshold model," that shows why and how resistance to therapy occurs in lung and melanoma cancer.

Tumours like melanoma and lung cancers can grow back shortly after therapy, but when they do they are made of genetically diverse sub-groups of malignant cell that are resistant to treatment.

The genetic diversity of the lung cancer  and melanoma tumour allow them to adapt to the treatment and resist it. The effect of a given drug with the selection of resistance-causing alterations in DNA, resulting in significant implications for the treatment of cancer patients.

The way the drugs are administered during therapy can have a critical impact on the outcome of the response to treatment; intermittent administration enables simultaneous delivery of multiple targeted therapies while maintaining lower toxicity.
          haleplushearty.blogspot.com