metastasis

USC study shows how tumor cells in the bloodstream can target distant organs

/ Yimy Villa / Leave a comment

Various types of cancer can become particularly aggressive and difficult to treat once they spread from their initial point of origin to other parts of the body. This unfortunate phenomenon, known as metastasis, can make treatment very challenging, decreasing the chance of survival for the patient.

In order to better understand this process, a CIRM supported study at USC looked at breast cancer cells circulating in the blood that eventually invade the brain. The findings, which appear in Cancer Discovery, shed light on how tumor cells in the blood are able to target a particular organ, which may enable the development of treatments than can prevent metastasis from occurring.

Dr. Min Yu

Dr. Min Yu and her lab at USC were able to isolate breast cancer cells from the blood of breast cancer patients whose cancer had already metastasized. The team then expanded the number of cancer cells through a process known as cell culture. These expanded human tumor cells were then injected into the bloodstream of animal models. It was found that these cells migrated to the brain as was predicted.

Upon further analysis, Dr. Yu and her lab discovered a protein on the surface of the tumor cells in the bloodstream that enable them to breach the blood brain barrier, a protective layer around the brain that blocks the passage of certain substances, and enter the brain. Additionally, Dr. Yu and her team discovered another protein inside the tumor cells that shield them from the brain’s immune response, enabling these cells to grow inside the brain.

In a news release in Science Magazine, Dr. Yu talks about how these findings could be used to improve treatment and prevention options for those with aggressive cancers:

“We can imagine someday using the information carried by circulating tumor cells to improve the detection, monitoring and treatment of the spreading cancers. A future therapeutic goal is to develop drugs that get rid of circulating tumor cells or target those molecular signatures to prevent the spread of cancer.”

CIRM has also funded a separate clinical trial related to the treatment of breast cancer related brain metastases.

UC Irvine scientists engineer stem cells to “feel” cancer and destroy it

/ Todd Dubnicoff / 3 Comments

By blocking cell division, chemotherapy drugs take advantage of the fact that cancer cells multiply rapidly in the body. Though this treatment can extend and even save the lives of cancer patients, it’s somewhat like destroying an ant hill with an atomic bomb: there’s a lot of collateral damage. The treatment is infused through the blood so healthy cells that also divide frequently – like those in hair follicles, the intestines and bone marrow – succumb to the chemotherapy. To add insult to injury, cancers often become resistant to these drugs and metastasize, or invade, other parts of the body. Sadly, this spreading of a cancer is responsible for 90% of cancer deaths.

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UCI doctoral students Shirley Zhang, left, and Linan Liu are co-leading authors of the study. Photo: UC Irvine

Developing more specific, effective anti-cancer therapies is the focus of many research institutes and companies. While some new strategies target cell surface proteins that are unique to cancer cells, a UC Irvine (UCI) team has devised a stem cell-based technique that can seek out and destroy breast cancer cells that have metastasized in the lungs of mice by sensing the stiffness of the surrounding tissue. The CIRM-funded study was published this week in Science Translational Medicine.

While cells make up the tissues and organs of our bodies, they also secrete proteins and molecules that form a scaffold between cells called the extracellular matrix. This cell scaffolding is not just structural, it also plays a key role in regulating cell growth and other functions. And previous studies have shown that at sites of tumors, accumulation of collagen and other proteins in the matrix increases tissue stiffness and promotes metastasis.

Based on this knowledge, the UCI team aimed to create a cell system that would release chemotherapy drugs in response to increased stiffness. It turns out that mesenchymal stem cells – which give rise to bone, muscle, cartilage and fat – not only migrate to tumors in the body but also activate particular genes in response to the stiffness of their local cellular environment.  The researchers engineered mesenchymal stem cells to carry a gene that codes for a protein involved in the activation of a chemotherapy drug which is given by mouth. They also designed the gene to turn on only when it encounters stiff, cancerous tissue. They called the method a mechanoresponsive cell system (MRCS).

To test the MRCS, mice were infused with human breast cancer cells, which metastasized or spread to the lung. The MRCS-engineered mesenchymal stem cells were infused through the blood and homed to the lungs where they activated the chemotherapy drug which caused localized killing of the tumor cells with minimal damage to lung tissue. When the MRSC stem cells were given to mice without tumors, no increase in tissue damage was seen, proving that the MRSC-induced chemotherapy drug is only activated in the presence of cancerous tissue and has few side effects.

In a press release, team leader Weian Zhao, explained that these promising results could have wide application:

Weian-Zhao2-757x1024

Weian Zhao
Photo: UC Irvine

“This published work is focused on breast cancer metastases in the lungs. However, the technology will be applicable to other metastases as well, because many solid tumors have the hallmark of being stiffer than normal tissue. This is why our system is innovative and powerful, as we don’t have to spend the time to identify and develop a new genetic or protein marker for every kind of cancer.”

 

The team envisions even more applications. The MRCS could be engineered to carry genes that would enable detection with imaging technologies like PET scans. In this scenario, the MRCS could act as a highly sensitive detection system for finding areas of very early metastases when current techniques would miss them. They could also design the MRCS to activate genes that code for proteins that can break down and soften the stiff cancerous tissues which may inhibit the ability for a tumor to spread.

UCLA scientists find new targets for late-stage prostate cancer

/ Karen Ring / Leave a comment

Prostate cancer, which currently affects 3 million men in the United States, is no longer a death sentence if caught early. The five-year survival rate is very high (~98%) because of effective treatments like hormone therapy, chemotherapy, surgery, and radiation—and for many men with slow progressing tumors, the wait-and-watch approach offers an alternative to treatment.

However, for those patients who have more aggressive forms of prostate cancer, where the tumors spread to other organs and tissues, the five-year survival rate is much lower (~28%) and standard therapies only work temporarily until the tumors become resistant to them. Thus there is a need for finding new therapeutic targets that would lead to more effective and longer-lasting treatments.

Kinases are ABL to cause cancer

We recently wrote a blog about prostate cancer featuring the work of a pioneer in cancer research, Dr. Owen Witte from the UCLA Broad Stem Cell Research Center. Dr. Witte is well known for his work on understanding the biology of blood cancers (leukemias) and the role of cancer stem cells. One of his key discoveries was that the cancer-causing BCR-ABL gene produces an overactive protein kinase that causes chronic myelogenous leukemia (CML).

Protein kinases are enzymes that turn on important cell processes like growth, signaling, and metabolism, but they also can be involved in causing several different forms of cancer. This has made some kinases a prime target for developing cancer drugs that block their cancer-causing activity.

New targets for late-stage prostate cancer

Recently, Dr. Witte’s interests have turned to understanding and finding new treatments for aggressive prostate cancers. He has been on the hunt for new targets, and this week, Witte and his group published a CIRM-funded study in the journal PNAS showing that a specific set of kinases are involved in causing advanced stage prostate cancer that spreads to bones.

They selected a group of 125 kinases that are known to be active in aggressive forms of human cancers. From this pool, they found that 20 of these kinases caused metastasis, or the spreading of cancer cells from the starting tumor to different areas of the body, when activated in mouse prostate cancer cells that were injected into the tail veins of mice.

To narrow down the pool further, they activated each of the 20 kinases in human prostate cancer cells and injected these cells into the tails of mice. They found that five of the kinases caused the cancer cells to leave the tail and metastasize into the bones. When they compared the activity of these five kinases in the late-stage and early-stage prostate cancer cells as well as normal prostate cells, they only saw activity of these kinases in the late-stage cancer cells.

Microscopic view of a hip bone (left) and a magnified view of the bone showing the metastasized prostate cancer tumor (T), healthy bone marrow (M) and bone (B). Image courtesy of the UCLA Broad Stem Cell Research Center.

Microscopic view of a hip bone (left) and a magnified view of the bone showing the metastasized prostate cancer tumor (T), healthy bone marrow (M) and bone (B). Image courtesy of the UCLA Broad Stem Cell Research Center.

New treatment option?

Witte and his colleagues concluded that these five kinases can cause prostate tumor cells to spread and metastasize into bones, and that targeting kinase activity could be a new therapeutic strategy for late-stage prostate cancer patients that have exhausted normal treatment options.

In a UCLA press release, Claire Faltermeier, the study’s first author and a medical and doctoral student in Witte’s lab commented:

Our findings show that non-mutated protein kinases can drive prostate cancer bone metastasis. Now we can investigate if therapeutic targeting of these kinases can block or inhibit the growth of prostate cancer bone metastasis.

 

Dr. Witte followed up by mentioning the promise of targeting kinase activity for late-stage prostate cancer:

Cancer-causing kinase activity has been successfully targeted and inhibited before. As a result, chronic myelogenous leukemia is no longer fatal for many people. I believe we can accomplish this same result with advanced stages of prostate cancer with a fundamental understanding of the cellular nature of the disease.

UCLA scientists Owen Witte and

UCLA scientists Owen Witte and Claire Faltermeier

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Mapping Metastasis: Scientists Discover how Cancer Cells Colonize Distant Organs

/ cirmweb / Leave a comment

How does cancer spread? How does it traverse from one organ to the next—often undetected—until it has colonized the far reaches of the human body? And more importantly, how can researchers stop this from happening?

These questions plague even the most renowned experts, but new research from scientists at Brown University has uncovered clues to cancers’ unique ability to invade our bodies—offering important insight into how we might develop tools to stop this disease’s most dangerous ability.

Cancer cells advance across a microchip designed to be an obstacle course for cells. The device sheds new light on how cancer cells invade and could be used to test drugs aimed at preventing cancer spread. [Credit: Ian Y. Wong / Brown University]

Cancer cells advance across a microchip designed to be an obstacle course for cells. The device sheds new light on how cancer cells invade and could be used to test drugs aimed at preventing cancer spread. [Credit: Ian Y. Wong / Brown University]

Reporting in this week’s issue of Nature Materials, biomedical engineer Dr. Ian Wong and his team devised a special microchip technology that tracks individual cancer cells as they navigate from one end of the chip to the other. Importantly, this tool uncovered how cancer cells hijack an otherwise normal cellular process to infect the body.

This process, called the epithelial-mesenchymal transition (or ‘EMT’) normally occurs in the developing embryo, when one type of cells, called epithelial cells, transforms into mesenchymal cells. Epithelial cells tend to clump together into larger groups, whereas mesenchymal cells can more easily and more quickly break away from the pack and travel individually. This transition is crucial to embryonic development, as it allows for cells to get to where they need to be at the appropriate time.

However, scientists have recently begun to hypothesize that cancer uses EMT as a tool to help it metastasize—traversing throughout the body and setting up shop in various tissues and organs. Metastasis is one of the biggest hurdles to eradicating cancer, and is responsible for 90% of all cancer-related deaths.

As Wong explained in yesterday’s news release:

“People are really interested in how EMT works and how it might be associated with tumor spread, but nobody has been able to see how it happens. We’ve been able to image these cells in a biomimetic system and carefully measure how they move.”

The research team used microchip technology to essentially build a microscopic ‘obstacle course,’ which cancer cells had to navigate. Made from a silicon wafer and tiny pillars just 10 micrometers in diameter and spaced so close together with just enough space for the cells to squeeze in between. Then, using fluorescent dye and time-lapse photography, they watched as the cells moved from one end of the chip to the other. According to Wong:

“We can track individual cells, and because the size and spacing of these pillars is highly controlled, we can start to do statistical analysis and categorize these cells as they move.”

This amazing video revealed that cells moved across the plate at two different speeds.

Most moved slowly, often clumping together, exhibiting classic epithelial cell behavior. But a minority of cells sped through the obstacle course individually—breaking away from the pack. These cells, Wong argues, have switched to mesenchymal cells after experiencing EMT.

“In the context of cell migration, EMT upgrades cancer cells from an economy model to a fast sports car. Our technology enabled us to track the motion of thousands of ‘cars’ simultaneously, revealing that…some sports cars break out of traffic and make their way aggressively to distant locations.”

These ‘breakaway’ cells are how cancer can reach, invade and, ultimately destroy, distant organs.

But this newfound knowledge also hints at a possible therapeutic strategy: developing a drug that reverses EMT in cancer cells, keeping them in clumps and slowing their progress.

“An interesting therapeutic strategy might be to develop drugs that downgrade mesenchymal ‘sports cars’ back to epithelial ‘economy models’ in order to keep them stuck in traffic, rather than aggressively invading surrounding tissues.’

Want to learn more about how cancer spreads? Check out our Solid Tumor Fact Sheet.