Exosome Scouts Help Tumors Populate Distant Organs

When certain types of cancer spread, they seem to prefer particular organs in the body, a choosiness that led Stephen Paget to propose the “seed and soil” hypothesis. This hypothesis, now more than 100 years old, suggests that different organs are somehow more receptive to certain types of cancer, just as different soils seem to allow some seeds, but not others, to find purchase.

While this hypothesis is as expressive as ever, it still lacks detail. It doesn’t suggest what mechanisms might drive organ-specific metastasis, or organotropic metastasis. The hypothesis, however, is being taken farther by researchers based at Weill Cornell Medicine. These researchers suggest that the old seed-and-soil idea, which sounds as haphazard as the dispersal of seeds by uncultivated plants, could be updated to describe a process that is more directed.

Essentially, a tumor metastasis may proceed the way settlers cultivate new land. First, scouts and pioneers are dispatched to identify fertile spots and develop basic infrastructure. Then, once the ground is prepared, settlers establish new communities.

In this scenario, the scouts are tumor exosomes. These exosomes are released by tumors in the millions, and they carry samples of the tumors’ proteins and genetic content. They fuse preferentially with cells at specific locations, and they ensure that recipient organs are prepared to host the tumor cells they represent.

Most important, this updated view of organotropic metastasis includes a mechanism to explain how exosomes are directed to specific organs. The exosomes, it turns out, are outfitted with particular sets of integrins, proteins that serve as a kind of destination label.

Supportive findings appeared October 28 in the journal Nature, in an article entitled, “Tumour exosome integrins determine organotropic metastasis.” This article described how the Weill Cornell researchers, in collaboration with scientists from the Memorial Sloan Kettering Cancer center and the Spanish National Cancer Research Centre (CNIO), examined exosomes from mouse and human lung-, liver-, and brain-tropic tumor cells. These exosomes were seen to fuse preferentially with resident cells at their predicted destinations, namely, lung fibroblasts and epithelial cells, liver Kupffer cells, and brain endothelial cells.

“Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis,” wrote the authors. “Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively.”

In other words, the study demonstrated the importance of integrins in metastatic nesting by blocking specific integrins in tumors that metastasize to specific organs. For example, when integrins were blocked in breast cancer, metastasis to lungs was reduced. Similarly, when integrins were blocked in pancreatic cancer, metastasis to liver was reduced.

In addition, the study showed that a tumor could be “tricked” by changing the integrin destination code of its exosomes. For example, a tumor that would normally go to the bones could be directed to the lungs instead.

“The integrin-specific signature that we identified may have significant value clinically, serving as a prognostic indicator for metastasis to specific organ sites,” said senior author David Lyden, M.D., Ph.D., the Stavros S. Niarchos Professor in Pediatric Cardiology and a professor of pediatrics and of cell and developmental biology at Weill Cornell Medicine. “Instead of waiting for late-stage metastasis, we can now initiate preventative strategies at an earlier point of disease progression with the hope of preventing its spread. This really changes the treatment paradigm.”

“Good” Protein Actually Promotes Liver Cancer.

  • Scientists at the University of Iowa say they have identified an unexpected molecular link between liver cancer, cellular stress, and these health problems that increase the risk of developing this cancer. Their study (“The Stress-Regulated Transcription Factor CHOP Promotes Hepatic Inflammatory Gene Expression, Fibrosis, and Oncogenesis”) is published in PLOS Genetics. It shows that a protein called CHOP, which had previously been thought to generally protect against cancer, actually promotes liver cancer in mice and may do the same in humans.

    “Good” Protein Actually Promotes Liver Cancer

    “Obesity, alcoholism, and viral hepatitis are all known independently to cause cellular stress and to induce expression of CHOP,” said Thomas Rutkowski, Ph.D., assistant professor of anatomy and cell biology in the UI Carver College of Medicine and senior study author. “So this finding suggests a biological pathway that links those ‘upstream’ health problems to liver cancer at the end.”

    CHOP is a transcription factor that is produced when cells experience certain kinds of stress. It is known to promote cell death. Usually, factors that promote cell death protect against cancer by causing damaged cells to die.

    The study shows that, despite its role in cell death, CHOP actually is elevated in liver tumor cells in mice. Furthermore, mice without CHOP are partially protected from liver cancer, developing fewer and smaller tumors than the normal mice in response to liver cancer-causing drugs. The mice without CHOP also had less liver scarring and inflammation than mice with the protein.

    “We show that CHOP expression is up-regulated in liver tumors in human HCC [hepatocellular carcinoma] and two mouse models thereof. CHOP-null mice are resistant to chemical hepatocarcinogenesis, and these mice exhibit attenuation of both apoptosis and cellular proliferation,” wrote the investigators. “CHOP-null mice are also resistant to fibrosis, which is a key risk factor for HCC. Global gene expression profiling suggests that deletion of CHOP reduces the levels of basal inflammatory signaling in the liver. Our results are consistent with a model whereby CHOP contributes to hepatic carcinogenesis by promoting inflammation, fibrosis, cell death, and compensatory proliferation.”

    “We turned out to be completely wrong about CHOP. We found that it contributes to the development of liver cancer in mice and is associated with liver cancer in humans,” continued Dr. Rutkowski. “CHOP is indeed killing cells, just as we thought it would, but we think the consequence of this killing is not the prevention of tumors, but instead the stimulation of inflammatory signals in the liver that cause excessive proliferation of other cells.”

    Having implicated CHOP as a contributing factor in liver cancers associated with obesity, alcoholism, and hepatitis, Dr. Rutkowski next wants to learn whether CHOP acts early in the process of tumor formation or if it plays a role in helping established tumors to grow. He also is interested in identifying the other proteins that partner with CHOP to promote liver cancer.

    “This discovery opens up an avenue into a new pathway that promotes liver cancer,” explained Dr. Rutkowski. “Once we know what those other genes are that interact with CHOP, then maybe we can find a druggable target molecule. The hope is that down the line scientists will be able to convert that finding into something therapeutically useful for patients.”

Cancer diversity ‘threatens drugs’

A single tumour can be made up of many separate cancers needing different treatments, say researchers.

A team at the Institute of Cancer Research, London, have developed a new technique for measuring the diversity within a cancer.

Cancer cells

They showed “extraordinary” differences between cancerous cells and say new targeted drugs may fail as they may be unable to kill all the mutated tissue.

Experts said the findings would have “profound implications” for treatments.

A tumour starts as a single cell, which acquires mutations and eventually divides uncontrollably. But that is not the end of the process.

Cancerous cells continue to mutate and become more aggressive, move round the body and resist drugs.

“Start Quote

Every patient has a completely new tree and doesn’t have one cancer, they have multiple cancers”

Prof Mel Greaves Institute of Cancer Research

This process is chaotic and results in a “diverse” tumour containing cancerous cells that have mutated in different ways.

“This has huge implications for medicine,” researcher Prof Mel Greaves told the BBC.

His team at the Institute of Cancer Research investigated cancer diversity in five children with leukaemia. They compared mutations in individual cancerous cells with a known database of mutations.

Their results, published in the journal Genome Research, showed patients had between two and 10 genetically distinct leukaemias.

Prof Greaves said: “Every patient has a completely new tree and doesn’t have one cancer, they have multiple cancers.

“This is really a technical advance to get at this extraordinary complex diversity, it helps explain why we have such difficulty with advanced diseases.”

Tree of cancer

Scientists compare cancer diversity to a tree. The initial mutations – the trunk – will be common to all cancer cells. But then the tumour branches out.

Drugs need to target the trunk of a tumour say researchers

It means a treatment that targets one “branch” or sub-clone of the cancer might slow the disease, but they will never stop it.

Prof Charles Swanton, who researches diversity at the University College London Cancer Institute, told the BBC: “We call it pruning the branches not cutting down the tree, targeted therapies will remove some of the sub-clones, but chopping down the tree is hard to do.”

“Start Quote

The bottom line is we need to understand cancer diversity to limit further adaptations, reduce the pace of evolution and prolong the activity of drugs”

Prof Charles Swanton UCL

The study investigated leukaemia as it is less diverse than other types of cancer. Other tumours such as melanoma could feasibly be made of hundreds of branches.

Prof Greaves says one implication of the research is that therapies need to be developed which target the trunk of the tumour and that current targeted therapies being researched may not tackle advanced cancers.

Another idea he suggests is focusing on the cancer’s surroundings as well.

“If it is diversifying like species in a habitat, why not target the habitat – the blood vessels supplying oxygen or inflammation. There’s a lot of interest in that,” he said.

The research also emphasises the importance of catching cancers early before they have become too diverse to treat.

Prof Charles Swanton argues: “The bottom line is we need to understand cancer diversity to limit further adaptations, reduce the pace of evolution and prolong the activity of drugs.”

Prof Chris Bunce, the research director at Leukaemia and Lymphoma Research, commented: “We are beginning to understand how unique and complex each patient’s cancer is and the profound implications that this can have on the success of treatment.

“This study significantly advances our understanding of how cancers start and evolve.”

Too Much Information? Geneticist Mark Robson Discusses Accidental Genetic Findings.

Genetic testing of tumors is becoming increasingly common in cancer care. The molecular alterations found in a tumor can provide critical information for making an accurate diagnosis and determining the best treatment.

Although current clinical testing usually focuses on a panel of specific mutations, cancer centers are developing programs to analyze entire cancer genomes routinely — an approach made possible by cheaper sequencing costs — in order to individualize care. This process raises a thorny issue: What happens when a genome analysis of a person’s tumor reveals that he or she is at risk for developing a different type of cancer or other disease?

Recently, Memorial Sloan-Kettering Clinical Genetics Service Chief Kenneth Offit, Clinical Genetics Service Clinic Director Mark E. Robson, and researcher Yvonne Bombardpublished a viewpoint in the Journal of the American Medical Association regarding this question of incidental genetic findings, which cancer researchers have dubbed the “incidentalome.”

We asked Dr. Robson to discuss some of the issues surrounding accidental genetic findings and what Memorial Sloan-Kettering is doing to address them.

What is an example of a genetic variation that might be discovered by accident while sequencing the genome of a patient’s tumor?

For instance, you could be sequencing a lung cancer tumor in search of an EGFR mutation to target with an anticancer drug, and find a mutation in BRCA1, which is associated with increased risk for breast and ovarian cancer. Since most of a tumor’s DNA sequence is identical to the sequence of a normal cell from that same patient, this additional variation is probably inherited — and is what is called a germline mutation.

In that situation, are you obligated to inform the patient? It’s a very complex question. There are many variables to consider, such as individual preference, whether anything can be done to control risk, and whether other people — such as close relatives — may be affected.

Has this actually become a problem for doctors and researchers, or is it still a hypothetical situation for now?

Right now, most clinical testing of tumors is for a relatively limited number of specific mutations, not the full genome. But soon we’re going to be testing for a much broader panel of genes, increasing the chances of incidental findings.

On the research side, it’s quickly becoming an issue. Many tumor samples that have been stored in tissue banks for years or decades are now being fully sequenced. If incidental discoveries are made during that process, is there an obligation to try to find those patients and inform them? This has not been established, and there are obvious practical barriers. We need to lay the intellectual groundwork now for how we’re going to respond to these questions.

What steps have been taken at Memorial Sloan-Kettering to address the issue?

This summer, our Institutional Review Board (IRB), which oversees all of our patient-related research, updated part of our patient consent policy. When patients agree to have a tissue sample taken, they are asked whether they are open to being re-contacted if an investigator finds something that might affect their health.

Under the new procedure, if a researcher finds something that might be important to communicate to the patient, the specific question will be put before the IRB and carefully considered. If there is agreement the information should be conveyed, and the patient has indicated that he or she wants to be re-contacted, we’ll reach out to that person. We think this protects the people participating in our studies without restricting important research.

With all the genetic research taking place at Memorial Sloan-Kettering, is the IRB facing a deluge of these cases?

So far, no. The way the analyses are being conducted is that the computer looks for mutations in specific spots and subtracts all other information about the inherited genetic sequence before the investigator sees it. In other words, if you have genetic variants present in the tumor that are also in the normal cells, they are being filtered out by the software. The investigator ends up seeing variants that are only in the tumor.

As we pointed out in the JAMA paper, this is one way of limiting potential incidentalome issues.

But some researchers don’t have the germline DNA sequence available for comparison purposes, so while sequencing the tumor they see potentially relevant variations. For example, they could be sequencing a prostate cancer genome and see a mutation in theBRCA1 gene, which increases risk of other cancers.

The question becomes, under what circumstances do you tell the patient, and what about the patient’s siblings or children who may carry the mutation as well? In addition, sometimes multiple variants associated with disease risk may be found — and how do we provide counseling for all of them at once?

Have you gotten a sense from patients about what their preference usually is regarding being informed of these incidental genetic discoveries?

Commonly, people say, “I want to know everything,” but the devil’s in the details when you start considering the risk for diseases that can’t be prevented or treated. We are setting up focus groups of patients and unaffected people to try to understand how people think when they are confronted with these situations and how they prioritize different types of genetic information. We also have an active IRB protocol in which we are giving people who had their sequence determined as part of research studies the opportunity to learn their results.

Right now, it’s not clear what the dividing lines are. We want to reach a point where mutations are sorted into different categories, where certain incidental findings are nearly always appropriate to communicate to patients, others almost never so, and some require more context to determine.

We’re moving from the traditional model of asking patients if they would like to hear the results of a specific test before that test is performed, to this brave new world where we’re trying to help people make decisions about genetic information revealed by accident that is not possible to fully anticipate. It’s a very complicated issue, but it also offers a tremendous opportunity to benefit patients.

If you are interested in participating in the focus group, call 646-888-4867. Everyone is welcome, including patients, relatives, Memorial Sloan-Kettering employees, and the general public. No sequencing is provided.

Source: MSKCC




Football-shaped particles bolster the body’s defense against cancer

Researchers at Johns Hopkins have succeeded in making flattened, football-shaped artificial particles that impersonate immune cells. These football-shaped particles seem to be better than the typical basketball-shaped particles at teaching immune cells to recognize and destroy cancer cells in mice.


“The shape of the really seems to matter because the stretched, ellipsoidal particles we made performed much better than spherical ones in activating the immune system and reducing the animals’ tumors,” according to Jordan Green, Ph.D., assistant professor of biomedical engineering at the Johns Hopkins University School of Medicine and a collaborator on this work. A summary of the team’s results was published online in the journal Biomaterials on Oct. 5.

According to Green, one of the greatest challenges in the field of cancer medicine is tracking down and killing once they have metastasized and escaped from a tumor mass. One strategy has been to create tiny artificial capsules that stealthily carry toxic drugs throughout the body so that they can reach the escaped tumor cells. “Unfortunately, traditional chemotherapy drugs do not know healthy cells from tumor cells, but immune system cells recognize this difference. We wanted to enhance the natural ability of T-cells to find and attack tumor cells,” says Jonathan Schneck, M.D., Ph.D., professor of pathology, medicine and oncology.

In their experiments, Schneck and Green’s interdisciplinary team exploited the well-known immune system interaction between antigen-presenting cells (APC) and T-cells. APCs “swallow” invaders and then display on their surfaces chewed-up protein pieces from the invaders along with molecular “danger signals.” When circulating T-cells interact with APCs, they learn that those proteins come from an enemy, so that if the T-cells see those proteins again, they divide rapidly to create an army that attacks and kills the invaders.

According to Schneck, to enhance this natural process, several laboratories, including his own, have made various types of “artificial APCs”—tiny inanimate spheres “decorated” with pieces of tumor proteins and danger signals. These are then often used in immunotherapy techniques in which are collected from a cancer patient and mixed with the artificial APCs. When they interact with the patient’s T-cells, the T-cells are activated, learn to recognize the tumor cell proteins and multiply over the course of several days. The immune cells can then be transferred back into the patient to seek out and kill .

The cell-based technique has had only limited success and involves risks due to growing the cells outside the body, Green says. These downsides sparked interest in the team to improve the technique by making biodegradable artificial APCs that could be administered directly into a potential patient and that would better mimic the interactions of natural APCs with T-cells. “When immune cells in the body come in contact, they’re not doing so like two billiard balls that just touch ever so slightly,” explains Green. “Contact between two cells involves a significant overlapping surface area. We thought that if we could flatten the particles, they might mimic this interaction better than spheres and activate the T-cells more effectively.”

To flatten the particles, two M.D./Ph.D. students, Joel Sunshine and Karlo Perica, figured out how to embed a regular batch of spherical particles in a thin layer of a glue-like compound. When they heated the resulting sheet of particles, it stretched like taffy, turning the round spheres into tiny football shapes. Once cooled, the film could be dissolved to free each of the microscopic particles that could then be outfitted with the tumor proteins and danger signals. When they compared typical spherical and football-shaped particles—both coated with tumor proteins and danger signals at equivalent densities and mixed with T-cells in the laboratory—the T-cells multiplied many more times in response to the stretched particles than to spherical ones. In fact, by stretching the original spheres to varying degrees, they found that, up to a point, they could increase the multiplication of the T-cells just by lengthening the “footballs.”

When the particles were injected into mice with skin cancer, the T-cells that interacted with the elongated artificial APCs, versus spherical ones, were also more successful at killing tumor cells. Schneck says that tumors in mice that were treated with round particles reduced tumor growth by half, while elongated particles reduced tumor growth by three-quarters. Even better, he says, over the course of a one-month trial, 25 percent of the mice with skin cancer being treated with elongated particles survived, while none of the mice in the other treatment groups did.

According to Green, “This adds an entirely new dimension to studying cellular interactions and developing new artificial APCs. Now that we know that shape matters, scientists and engineers can add this parameter to their studies,” says Green. Schneck notes, “This project is a great example of how interdisciplinary science by two different groups, in this case one from biomedical engineering and another from pathology, can change our entire approach to tackling a problem. We’re now continuing our work together to tweak other characteristics of the artificial APCs so that we can optimize their ability to activate T- inside the body.”

Source: Johns Hopkins University School of Medicine

Cornell dots show promise in targeting cancer cells during surgery.

The U.S. Food and Drug Administration (FDA) has approved the first clinical trial of a new technology that uses radiolabeled nanoparticles to brighten cancer cells so they can be detected by a PET-optical imaging camera.

Researchers from Memorial Sloan-Kettering Cancer Center (MSKCC) and Cornell University are collaborating with Hybrid Silica Technologies, a Cornell start-up company, and Dutch optical imaging developer O2view on the project and clinical trial.

The FDA’s investigational new drug (IND) approval for the study represents the first inorganic particle platform of its class to be used for multiple clinical indications, according to co-researcher Dr. Michelle Bradbury, a neuroradiologist at MSKCC and assistant professor of radiology at Weill Cornell Medical College.

The trial will explore the applications of cancer targeting and future therapeutic diagnostics, as well as cancer disease staging and tumor burden assessment through lymph node mapping.

Multiple applications

“Cancer has largely been the heavy hitter for nanoparticle probes, and I think there are overlaps with other diseases where institutions could make use of such types of particles,” Bradbury toldAuntMinnie.com. “We are developing the [therapeutic diagnostic] probes and using them for surgical applications, mainly lymph node mapping.”

The so-called “Cornell dots” are silica spheres approximately 6 nm in diameter that enclose several dye molecules. The silica shell, which is essentially glass, is chemically inert and small enough to pass through the body and exit in the urine. For clinical applications, the dots are coated with neutral molecules — polyethylene glycol (PEG) — so the body will not recognize them as foreign substances and activate a patient’s immune system to reject them.

To make the nanoparticles adhere to tumor cells, organic molecules that bind to tumor surfaces or specific locations within tumors can be attached to the PEG shell. When exposed to near-infrared light, the dots become brighter and help identify the targeted cancer cells.

Nanoparticle half-life

Nanoparticles in general can linger in the bloodstream for many hours and even days, depending on their size. Given their 6-nm size, the nanoparticles have a half-life of approximately six hours in the bloodstream before evacuation through the kidneys. “Within a 24-hour period,” Bradbury said, “50% may be cleared through the kidneys.”

Among the researchers’ goals in this trial is to validate the pharmacokinetics and dosimetry of the nanoparticles and PET-optical imaging technology for safe use in humans. Researchers also will collect blood and urine samples to see how different parts of the body, besides organs, react to the nanoparticles.

The study will include five metastatic melanoma patients as its first enrollees. “If all goes well with a few patients, we hope to proceed with a targeted study,” Bradbury said.

Surgical information

The technology, the researchers believe, could be particularly beneficial during surgical treatment, allowing surgeons to see the invasive or metastatic spread to lymph nodes and distant organs and illustrating the extent of treatment response.

Initially, the surgical applications will include cancer within the complex area of the head and neck. With the help of the nanoparticles and PET-optical imaging camera, surgeons will be able to detect the activity of the lymph nodes.

Currently, Bradbury explained, physicians have little or nothing to refer to during surgery other than a preclinical scan — and compared to the scan, the patient is now in a totally different position on the table.

“How would they know where they are in the neck?” she asked. “They just don’t [know], so they want tools so they can see what they are doing and see the nodes in relation to vital structures, such as nerves. They don’t want to pick up activity from a lymph node plus an adjacent tumor, which would be easy to do, if you don’t know where you are exactly.”

Nanoparticles in mice

Researchers have already had some success with the nanoparticles and the PET-optical imaging technology in a preclinical study in mice. Among the conclusions is that the nanoparticles have been “optimized for efficient renal clearance” and “concurrently achieved specific tumor targeting” (Journal of Clinical Investigation, July 2011, Vol. 121:7, pp. 2768-2780).

In addition, the multimodal silica nanoparticles exhibit “what we believe to be a unique combination of structural, optical, and biological properties,” wrote lead study authors Dr. Miriam Benezra and Dr. Oula Penate-Medina and colleagues.

To be clinically successful, the group added, the “next generation of nanoparticle agents should be tumor selective, nontoxic, and exhibit favorable targeting and clearance profiles. Developing probes meeting these criteria is challenging, requiring comprehensive in vivo evaluations.”

Source: http://www.auntminnie.com

Lung Cancer Signatures in Blood Samples May Aid in Early Detection.

Lung cancer is one of the most common and deadly types of cancer. Mouse models of lung cancer recapitulate many features of the human disease and have provided new insight about cancer development, progression and treatment. Now, a new study published by Cell Press in the September 13th issue of the journal Cancer Cell identifies protein signatures in mouse blood samples that reflect lung cancer biology in humans.

The research may lead to better monitoring of tumor progression as well as blood based early detection strategies for human lung cancer that could have a substantial impact on disease prognosis.

“In our study, we applied a comparative strategy of genetically engineered mouse models of cancer and integrated data at the genome and protein levels to uncover lung cancer signatures in blood samples that reflect different types of lung cancer, or that reflect signaling pathways driving tumor development,” says senior study author, Dr. Samir M. Hanash, from the Fred Hutchinson Cancer Research Center in Seattle. In order to identify blood protein signatures common to lung cancer, Dr. Hanash and colleagues looked at the proteins in the blood plasma of several different mouse lung tumor models and compared the proteins with those in models of other types of tumors.

The researchers identified individual protein signatures for molecularly distinct types of lung cancer and discovered that the networks of proteins provided insight into the genes that drive tumor development. Further, they identified proteins which were restricted to the blood samples from the lung cancer models and were not previously linked with lung cancer.

The authors went on to demonstrate the relevance of the protein signatures identified in the mouse models to human lung cancer. “We obtained evidence for concordant findings in human lung cancer cell lines and in plasmas collected from subjects with lung cancer at the time of diagnosis and in blood samples collected from asymptomatic subjects prior to diagnosis. These findings point to the power of integrating multiple types of studies and data to uncover lung cancer markers and may lead to early detection strategies for humans as well as strategies for monitoring tumor status in patients with the disease,” says Dr. Hanash.

Source: http://www.sciencedaily.com


Gene Involved in Lung Tumor Growth Identified.

Lung cancer researchers at St. Joseph’s Hospital and Medical Center in Phoenix, Ariz., in collaboration with researchers at the Translational Genomics Research Institute and other institutions, have identified a gene that plays a role in the growth and spread of non-small cell lung cancer tumors, opening the door for potential new treatment options.

The study, titled “Elevated Expression of Fn14 in Non-Small Cell Lung Cancer Correlates with Activated EGFR and Promotes Tumor Cell Migration and Invasion,” was published in the May 2012 issue of The American Journal of Pathology. Landon J. Inge, PhD, is the lead scientist in the thoracic oncology laboratory at St. Joseph’s Center for Thoracic Disease and Transplantation and was a member of the study’s research team.

Lung cancer is the leading cause of cancer deaths worldwide, and approximately 85 percent of these cancers are non-small cell lung cancers (NSCLC). Patients with NSCLC frequently have tumors with mutations in the epidermal growth factor receptor (EGFR) gene. When activated, this mutated gene leads to tumor development and growth. By studying lung cancer samples from patients who had undergone tumor resection, the researchers discovered that many patients with EGFR mutations also exhibited higher than normal levels of the gene fibroblast growth factor-inducible 14 (Fn14). The researchers believe that activation of EGFR can lead to increased expression and activity of the Fn14 gene.

The research team also discovered that while over-expression of Fn14 enhances lung tumor formation and metastasis, suppression of Fn14 reduces metastasis in NSCLC.

“Our data suggest that Fn14 levels can contribute to NSCLC cell migration and invasion,” says Dr. Inge. “Thus, tumor suppression through the targeting of Fn14 may prove to be a therapeutic intervention in NSCLC and other tumor types.”

The Fn14 gene has been found to be elevated in other types of tumors, as well, including glioblastoma and certain types of breast cancer, suggesting that Fn14 may be a therapeutic target for multiple cancer therapies.

Source: http://www.sciencedaily.com

Carbon Ion Radiotherapy Promising for Inoperable Spinal Tumors.

Carbon ion radiotherapy (CIRT) is a promising option for patients with spinal tumors that cannot be surgically removed, say researchers from Japan. This form of radiation is not currently available in the United States but is being tested in Germany.

CIRT can control cancer growth and prolong life in this “challenging” patient population, they report online today in the journal Cancer.

“In Japan, there are 3 working facilities providing [CIRT],” Reiko Imai, MD, PhD, from the Research Center Hospital for Charged Particle Therapy, National Institute of Radiological Sciences in Chiba, told Medscape Medical News. “The access is open for patients with unresectable sarcomas considered to be radioresistant tumors.”

Safe and Effective, Preserves QoL

Dr. Imai and colleagues carried out a retrospective review on data on 47 patients (24 men and 23 women) with 48 medically unresectable spinal sarcomas, excluding sacral tumors, who received CIRT between 1996 and 2011. Most of the patients (88%) had tumors located less than 5 mm from the spinal cord.

The median age of the patients was 54 years; they were enrolled in phase 1/2 and phase 2 clinical trials of CIRT for bone and soft tissue sarcoma. The applied dose ranged from 52.8 gray equivalents (GyE) to 70.4 GyE (median, 64.0 GyE) in 16 fixed fractions during a 4-week period.

The median follow-up was 25 months, and the median survival was 44 months (range, 5.2 to 148 months).

The researchers say CIRT yielded a 5-year local tumor control rate of 79% and overall and progression-free survival rates of 52% and 48%, respectively. None of the 15 patients with tumors measuring less than 100 cm3had a local recurrence.

No fatal toxicities occurred from treatment. One patient had a grade 3 late skin reaction, and 1 had a grade 4 late skin reaction. Seven patients suffered vertebral body compression, which was salvaged by surgical intervention. One patient had a grade 3 late spinal cord reaction.

Twenty-two of the 28 patients who were alive at last follow-up could walk without supportive devices.

Overall, these findings indicate that CIRT is “both safe and feasible,” the investigators say.

“In this analysis, we would like to emphasize that [CIRT] has the potential to overcome sarcomas and to preserve patients’ quality of life, even if the patients are not candidates for surgery,” Dr. Imai told Medscape Medical News.

“A String of Impressive Papers”

In a telephone interview with Medscape Medical News, David Kirsch, MD, PhD, who specializes in treating sarcoma but who was not involved in the study, noted that this group from Chiba, Japan, has been conducting CIRT trials since 1996 for medically inoperable bone and soft tissue sarcomas and has published “a string of impressive papers.” This includes a study reported by Medscape Medical News in 2002.

Dr. Kirsch is an associate professor of radiation oncology at Duke University School of Medicine in Durham, North Carolina. He thinks CIRT is “an important type of radiation; it has high linear energy transfer [LET] and the potential to kill cells by different mechanisms. These [new] results are good, and I think it’s an important modality to test head to head with standard radiation therapy or proton radiation therapy.”

CIRT is not currently available in the United States. “It would be really nice to have a carbon ion facility in the US and to do a randomized study to figure out if high LET radiation is really killing tumor cells that low LET radiation can’t; that’s kind of the theory,” Dr. Kirsch said.

The problem is cost. “To put up a carbon ion facility is about double the cost of proton therapy, which is also really expensive, although there are certain academic centers [in the United States] that are talking about building a carbon ion center,” Dr. Kirsch said.

He noted that a group in Germany is also testing CIRT against proton therapy in a randomized study.

Source: Medscape.com

The dual effects of delta(9)-tetrahydrocannabinol on cholangiocarcinoma cells: anti-invasion activity at low concentration and apoptosis induction at high concentration..


Currently, only gemcitabine plus platinum demonstrates the considerable activity for cholangiocarcinoma. The anticancer effect of Delta (9)-tetrahydrocannabinol (THC), the principal active component of cannabinoids has been demonstrated in various kinds of cancers. We therefore evaluate the antitumor effects of THC on cholangiocarcinoma cells. Both cholangiocarcinoma cell lines and surgical specimens from cholangiocarcinoma patients expressed cannabinoid receptors. THC inhibited cell proliferation, migration and invasion, and induced cell apoptosis. THC also decreased actin polymerization and reduced tumor cell survival in anoikis assay. pMEK1/2 and pAkt demonstrated the lower extent than untreated cells. Consequently, THC is potentially used to retard cholangiocarcinoma cell growth and metastasis.

Source: Pubmed