New cell mechanisms discovery key to stop the metastasis of breast cancer

Researchers from the University of Utah Huntsman Cancer Institute (HCI) therapy, not only to block the mechanism discovered cellular mechanism to the rest of the spread of breast cancer (metastatic), body. Research results was published in the online journal cell reports 1/2,.

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New cell mechanism discovery key to stopping breast cancer metastasis

Jan. 2, 2014 — Researchers from Huntsman Cancer Institute (HCI) at the University of Utah discovered a cellular mechanism that drives the spread of breast cancer to other parts of the body (metastasis), as well as a therapy which blocks that mechanism. The research results were published online in the journal Cell Reports on January 2.

"Genetic mutations do not drive this mechanism," said Alana Welm, PhD, senior author of the study, associate professor in the Department of Oncological Sciences, and an investigator at Huntsman Cancer Institute. "Instead, it's improper regulation of when genes turn on and off." The new discovery focuses on a protein called RON kinase (RON), which signals some areas of tumor cell DNA to become active. Normally, RON operates mostly during embryonic development and is not highly expressed in healthy adults. But in about 50 percent of breast cancer cases, RON becomes re-expressed and reprograms genes responsible for metastasis, making them active.

"If there's an entire program in the tumor cell that's important for metastasis, blocking one small part of that program, for example, the action of a single gene, will probably not be an effective strategy," said Welm. "But if you could find a way to turn off the entire program, you're more likely to have the desired effect. We found that inhibiting RON turns off the entire metastasis program in these tumor cells.

"No one has ever described a specific pathway driving this kind of reprogramming in metastasis, much less a way to therapeutically block it,' Welm added. "Also, RON has not previously been known to be involved in reprogramming gene expression."

Future work will include investigating the potential of detecting the RON-dependent program in tumor cells as a way to identify patients that are more likely to develop metastases and as a predictor of therapeutic response to drugs that inhibit RON.

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Change elevated circulating tumor cell metastasis BC before patients not beneficial chemotherapy.

Women with metastatic breast cancer, after first line chemotherapy in the amount of their blood circulating tumor cell (Ctc) were higher in the immediately switch to another chemotherapy did not improve overall survival or phase III clinical trials, 2013 at the San Antonio Breast Cancer Symposium University of Michigan comprehensive cancer time to progress, according to results announced by researchers in the Center, held 10-14 December.

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New function of two molecules involved in metastasis

Nov. 14, 2013 — Researchers from IMIM (Hospital del Mar Medical Research Institute) lead by Dr. Sandra Peiro have described a new function for two key molecules involved in tumor progression. Transcription factor SNAIL1 and enzyme LOXL2 are essential to Epithelial-Mesenchymal Transition (EMT); meaning the process by which tumor cells are able to move and reach other tissues. The study has been published in the Molecular Cell Journal and places enzyme LOXL2 as a possible therapeutic target to treat cancers such as breast, lung or skin cancer.

Transcription factors are proteins that regulate gene expression. They activate or deactivate a gene's function. Researchers at IMIM have studied the function of one of these transcription factors, Snail1, in mouse cells during the Epithelial-Mesenchymal Transition (EMT). Sandra Peiro, a researcher from the IMIM Research Group on Epithelial-Mesenchymal Transition and Tumor Progression explains: "EMT is a process consisting of converting epithelial cells, the ones covering the internal and external surfaces of the body, into what are known as mesenchymal cells. In this process, the cells acquire a series of new characteristics that enable them to migrate and resist apoptosis (programmed cell death), self-regenerate and, finally, invade neighboring tissues and reach other areas of the body. When this process occurs at the tumor epithelial cells, the resulting mesenchymal cells can migrate and generate metastases."

The study shows that during the transformation into mesenchymal cells, DNA, folded in to chromatin cell, must then become reorganized to adapt to the now cell functions. Transcription factors Snail1, through LOXL2 is in charge of this transformation. Therefore, any mechanism that is able to block it would prevent Epithelial-Mesenchymal Transition and thus a metastasis. "Our research is basic, and therefore, our findings cannot be applied immediately, but the fact that LOXL2 is a key element in the process and an enzyme makes it a firm candidate to be a therapeutic target, since its activity can easily be inhibited or blocked with the right drugs," says Sandra Peiro.

Previous studies by this group had described, for the first time, that LOXL2 was present at the cell nucleus and played a key role in tumor development. These new outcomes show that the functions of the genome are found to go far beyond the simple DNA sequence and that, therefore, it is necessary to integrate all levels of regulation to understand genome regulation. Right now, the challenge for the researchers is to study how the genome is organized spatially during a vital process in the development of cancer as EMT.

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Key link responsible for colon cancer initiation, metastasis

Nov. 11, 2013 — Chronic inflammation has long been known as a key risk factor for cancer -- particularly colon cancer -- but the exact mechanisms of how inflammation heightens the immune response, and ultimately influences the initiation and progression of cancer have remained elusive. It is well established that anti-inflammatory drugs, like aspirin, reduce the risk of colorectal cancer.

Now, an ASU research team led by Biodesign Institute executive director Dr. Ray DuBois, M.D., PhD, has shown that a key genetic culprit, called CXCR2, is implicated in the tumor formation, growth and progression in a mouse model of colon cancer.

"We have been trying for the past several years to understand the precise molecular links between inflammation and cancer, said DuBois. "We have demonstrated that CXCR2 mediates a critical step in the setup of the blood circulatory machinery that feeds tumor tissue. This provides an important new clue for the development of therapeutic targets to neutralize the effect of CXCR2 on colon cancer."

The DuBois' Laboratory for Inflammation and Cancer, which includes lead author Hiroshi Katoh, and colleagues Dingzhi Wang, Takiko Daikoku, Haiyan Sun, and Sudhansu K. Dey, published the results in the November 11 issue of Cancer Cell.

The results provide critical new clues toward the prevention of colorectal cancer, the second leading cause of cancer deaths in the U.S. Despite the availability of colonoscopy screening, the 5-year survival rate remains low, due to a large number patients presenting with advanced stages of the disease. Currently, there are no clinically available blood tests for the early detection of sporadic colon cancer.

Inflammation has long been associated with increasing one's risk for colon cancer. For instance, more than 20 percent of patients with a form of inflammatory bowel disease (IBD) develop colorectal cancer within 30 years of diagnosis. This colitis-associated cancer has a slow progression, but a very poor response to treatment and a high mortality rate.

Researchers have known that the broad mechanisms of cancer involve an interplay with the immune system response that includes: recruiting immune cells that influence the tumor microenvironment, escaping from host immunosurveillance and suppression, shifting of the host immune response, and tumor-associated angiogenesis to establish the blood supply.

For the study, the research team first "knocked-out" or removed the CXCR2 gene in mice, and found that the signs typically associated with inflammation were prevented. Furthermore, they demonstrated that CXCR2 dramatically suppressed colonic inflammation and the colitis associated tumor formation, growth and progression in mice.

CXCR2 decorates the outer part of immune cells called myeloid-derived suppressor cells, or MDSCs, that work to block the immune response of killer CD8+ T cells. In the knockout mice, without CXCR2 present, the MDSC cells could no longer migrate from the circulatory system to the colon, dodge the killer CD8+ T cell immune response, and feed the blood supply of the tumor environment. Furthermore, when they transplanted normal MDSC cells (with normal CXCR2) into the knockout mice, tumor formation was restored.

"These results provide the first genetic evidence that CXCR2 is required for recruitment of MDSCs into inflamed colonic mucosa and colitis-associated tumors," said DuBois.

For DuBois, who has devoted his career to unraveling the inflammatory circuitry responsible for colon cancer, the results help connect the dots between the immune system, inflammation and tumor formation and metastasis.

DuBois' team was the first to show that colorectal tumors contained high levels of the enzyme cyclo-oxygenase-2 (COX-2), a key step in the production of pro-inflammatory mediators such as prostaglandin E2 (PGE2). PGE2 triggers production of a CXCR2 molecule that fits into CXCR2 like a baseball into a glove's pocket and activates it. CXCR2, like the pied piper, recruits MDSCs from the bloodstream to sites of inflammation, causing the colon cancer tumors to evade the immune killer CD8+ T immune response.

"Our findings reveal not only how MDSCs are recruited to local inflamed tissues and tumor microenvironment and how local MDSCs contribute to colorectal cancer progression, but now also provide a rationale for developing new therapeutic approaches to subvert chronic inflammation- and tumor-induced immunosuppression by using CXCR2 antagonists and neutralizing antibodies," said DuBois.

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Microfluidic platform gives clear look at a crucial step in cancer metastasis

Sep. 20, 2013 — Cancer cells metastasize in several stages -- first by invading surrounding tissue, then by infiltrating and spreading via the circulatory system. Some circulating cells work their way out of the vascular network, eventually forming a secondary tumor.

While the initial process by which cancer cells enter the bloodstream -- called intravasation -- is well characterized, how cells escape blood vessels to permeate other tissues and organs is less clear. This process, called extravasation, is a crucial step in cancer metastasis.

Now researchers at MIT have developed a microfluidic device that mimics the flow of cancer cells through a system of blood vessels. Using high-resolution time-lapse imaging, the researchers captured the moments as a cancer cell squeezes its way through a blood vessel wall into the surrounding extracellular matrix. The process is "highly dynamic," as they write in a paper published in the journal Integrative Biology; a better understanding of it may help scientists identify therapies to prevent metastasis.

"Now that we have a model for extravasation, you can think about using it as a screen for drugs that could prevent it," says Roger Kamm, the Cecil and Ida Green Distinguished Professor of Biology and Mechanical Engineering at MIT. "We could take circulating tumor cells from a patient and subject those cells to a handful of factors or drugs. That's ultimately what we'd like to do, but in the process we're learning a lot as we go along."

Kamm's co-authors on the paper include graduate students Michelle Chen, Jordan Whisler and Jessie Jeon.

Seeding blood vessels

As tumor cells make their way through the circulatory system, some "arrest," or pause at a particular location, adhering to a blood vessel's wall -- the first stage of extravasation. Scientists have thought that this cell arrest occurs in one of two ways: A cell may send out sticky projections that grab onto the vessel lining, or it may be too big to pass through, literally becoming trapped within the vessel.

To investigate which possibility is more likely, the researchers grew a network of tiny blood vessels from a solution of human umbilical-cord endothelial cells. They injected a solution containing vascular cells into a small microfluidic device containing a reservoir of hydrogel, along with growth factors normally present in the developing circulatory system. Within days, an intricate system of microvessels took shape, with each about one millimeter long and 10 to 100 microns in diameter -- dimensions similar to the body's small capillaries.

The group then pumped tumor cells through the vascular network, using a line of breast cancer cells known to be particularly invasive. Using high-resolution confocal microscopy, the team watched as tumor cells flowed through the miniature circulatory system. They observed that the majority of cells that arrested along a vessel did so due to entrapment -- that is, they simply became stuck.

A tumor cell finds a way out

With time-lapse images, the researchers took a closer look at the progression of events following cell arrest. Once a tumor cell becomes trapped, they observed that it sends out long, thin filaments that push against a vessel wall, eventually creating a small hole in the endothelial lining. More and more of the cell squeezes through as the holes give way, and eventually, even the cell's nucleus -- thought to be a relatively rigid, nondeformable structure -- is able to escape.

To their surprise, the researchers found that the nucleus made it through the vessel wall earlier and more quickly than they anticipated, squeezing through in about 15 minutes -- "a tiny chunk of the time it takes for this entire cell to extravasate," Chen notes.

Interestingly, Chen points out, once a tumor cell has completely exited a blood vessel, the endothelium appears to heal itself, closing the gaps that the cell initially created. "That suggests that the endothelial barrier has some kind of active role in repairing itself after this invasion by the tumor cell," Chen says.

In addition to observing the extravasation of single tumor cells, the group also looked at the behavior of cell clusters -- two or more cancer cells that accumulate in a blood vessel. From their observations, the researchers found that almost 70 percent of cell clusters broke through a blood barrier, compared with less than 10 percent of single cells.

But some cells that make it out of the circulatory system may still fail to metastasize. To see whether a cell's ability to extravasate correlates with its metastatic potential, the group compared the efficiency of extravasation of different cancer cell lines. The lines included breast cancer cells, cells from fibrosarcoma (a cancer of the connective tissue), and a line of nonmetastatic cancer cells.

Sure enough, the team observed that the most metastatic cells (fibrosarcoma cells) were also the most likely to extravasate, compared with breast cancer and nonmetastatic cells -- a finding suggesting that targeting drugs to prevent extravasation may slow cancer metastasis.

Going forward, the group is looking into how likely a given cancer cell is to proliferate and aggregate with others once it has exited into the surrounding tissue. The researchers are modeling various tissues within the microfluidic platform, including bone, to study how cancer cells form the beginnings of a secondary tumor.

"Although this platform isn't an in-vivo platform and obviously can't capture all the aspects that happen in vivo, we've come a lot closer to creating an in-vitro platform that's even more physiologically relevant, high-resolution and high-throughput than a lot of previous platforms," Chen says.

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