The Way Doctors Treat Patients With Cancer And Autoimmune Diseases Could Change Following New Discovery

Researchers in the Faculty of Medicine & Dentistry at the University of Alberta have made an important discovery that provides a new understanding of how our immune system "learns" not to attack our own body, and this could affect the way doctors treat patients with autoimmune diseases and cancer.

When patients undergo chemotherapy for cancer or as part of experimental therapies to treat autoimmune diseases such as diabetes and lupus, the treatment kills the patients' white blood cells. What can be done afterwards, is to give these patients blood stem cells through transplantation. Stem cells are taken from patients then injected back into them - with the theory being that the patients' immune system won't attack their own cells, and the stem cells can get to work healing their bodies.

But U of A medical researchers Govindarajan Thangavelu, Colin Anderson and their collaborators discovered that if a particular molecule is not working properly in T-cells, the body will attack itself. This is significant for stem-cell transplantation treatment because it means the immune systems of the patients could consider their own cells "foreign" and initiate an attack.

"So your own cells would be killing you," says Thangavelu, a PhD student specializing in immunology, who was the first author in the research study, which was recently published in the peer-reviewed Journal of Autoimmunity. "What we found is if this molecule is absent in T-cells, if the pathway isn't intact, it will cause severe autoimmunity to the subject's own body. In essence, subjects become allergic to their own cells."

Anderson, an associate professor with the Alberta Diabetes Institute and Principal Investigator added: "The ability of our immune system to attack dangerous microbes while not attacking our own cells or tissues is a delicate balance. Restarting the immune system after wiping it out in patients with autoimmune diseases or cancer requires re-establishing this appropriate balance. We discovered that a particular immune system molecule is critical to prevent the immune system from attacking our own cells or tissues when the immune system is restarted. If that molecule is missing, the immune system will wreak havoc on the body."

T-cells are supposed to protect people and animals from things invading their bodies. But this research demonstrates if these cells become unregulated because they are missing a molecule, it can lead to autoimmunity - particularly dangerous in scenarios where patients have lost white blood cells when they are being treated for autoimmune diseases or cancer.

Thangavelu has won awards for this research. He was invited to present his work at an international conference of immunology in Japan last year. He has also travelled to the United Kingdom to talk about his findings with the medical community.

This research was funded by: the Juvenile Diabetes Research Foundation, the Canadian Institutes of Health Research, Alberta Innovates-Health Solutions and the Alberta Diabetes Institute.

Source:
Raquel Maurier
University of Alberta Faculty of Medicine & Dentistry

Cell Of Origin Found For Squamous Cell Cancer

Squamous cell cancers, which can occur in multiple organs in the body, can originate from hair follicle stem cells, a finding that could result in new strategies to treat and potentially prevent the disease, according to a study by researchers with UCLA's Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Researchers also found that the progeny of those cells, although just a few divisions away from the mother hair follicle stem cells, were not capable of forming squamous cell cancers. Further studying why those progeny, called transit amplifying cells, can't develop cancer could provide vital clues to how squamous cell cancers originate, said William Lowry, an assistant professor of molecular, cell and developmental biology in Life Sciences and senior author of the study.

The study, conducted in mouse models, appears the week of April 18 in the early online edition in the peer-reviewed journal the Proceedings of the National Academy of Sciences (PNAS).

It had been suggested in the literature that squamous cell cancers could arise from the hair follicle, but it was not clear what cell type within the follicle was responsible. This is the first time two distinct cell types in the skin have been compared and contrasted for their ability to develop squamous cell cancers, said Lowry, who is a Jonsson Cancer Center and Broad Stem Cell Research Center scientist.

"It was surprising that the progeny of these stem cells, which are developmentally more restricted, could not develop cancers when the mother stem cells could," said Lowry. "There is something fundamentally different between the two, and it's important that we figure out why one type of cell was able to develop cancer and the other was not. The insights we gain will tell us how these cancers arise in the first place, and could provide us with a wealth of novel targets we could go after to prevent the cancer before it starts."

A type of non-melanoma skin cancer, these cancers form in squamous cells, thin, flat cells found on the surface of the skin, the lining of the hollow organs of the body and the passages of the respiratory and digestive tracts. Squamous cell cancers occur in the skin, lips, mouth, esophagus, bladder, prostate, lungs, vagina, anus and cervix. Despite the common name, these cancers are unique malignancies with significant differences in manifestation and prognosis.

In this study, Lowry and his team sought to determine which cells of the epidermis, or skin, could give rise to squamous cell cancer. They wanted to find out if skin stem cells had properties than made them more prone to develop tumors than non-stem cells, said Andrew White, a post-doctoral fellow in Lowry's lab and first author of the study.

"Adult stem cells are long-lived and can acquire mutations that can cause cancer, but they also have intrinsic properties for self-renewal that are similar to cancer that could make them more tumor prone," White said.

Lowry and his team delivered genetic hits - adding an oncogene that is known to cause cancer and removing a tumor suppressor gene - to the hair follicle stem cells and the transit amplifying cells in two groups of mice and waited to see which developed cancer. Only the mice that received the genetic hits in the hair follicle stem cell population developed squamous cell cancer.

Going forward, White will molecularly profile the hair follicle stem cells and the transit amplifying cells to determine what string of biologic events occur when the cancer-causing genes are delivered. The differences between the two will be illuminating, Lowry said.

"We hope that this will lead to much more specific therapies that target cancer initiation rather than treating the disease once it's established," Lowry said. "If we're lucky, a drug may already exist that will hit a target we identify."

The four-year study was funded by the Jonsson Cancer Center Foundation, a training grant from the California Institute for Regenerative Medicine, the National Institutes of Health, the American Cancer Society, the University of California Cancer Research Coordinating Committee and the Maria Rowena Ross Chair in Cell Biology and Biochemistry.

A Belgium-based team also came to similar conclusions using slightly different methods, confirming the UCLA results. That study is published alongside Lowry's in PNAS.

The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA's Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.

Source:
UCLA's Jonsson Comprehensive Cancer Center

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Scientists Identify A Surprising New Source Of Cancer Stem Cells

Whitehead Institute researchers have discovered that a differentiated cell type found in breast tissue can spontaneously convert to a stem-cell-like state, the first time such behavior has been observed in mammalian cells. These results refute scientific dogma, which states that differentiation is a one-way path; once cells specialize, they cannot return to the flexible stem-cell state on their own.

This surprising finding, published online this week in the Proceedings of the National Academy of Sciences (PNAS), may have implications for the development of cancer therapeutics, particularly those aimed at eradicating cancer stem cells.

"It may be that if one eliminates the cancer stem cells within a tumor through some targeted agent, some of the surviving non-stem tumor cells will generate new cancer stem cells through spontaneous de-differentiation," says Whitehead Founding Member Robert Weinberg. Cancer stem cells are uniquely capable of reseeding tumors at both primary and distant sites in the body.

During differentiation, less-specialized stem cells mature into many different cell types with defined functions. These differentiated cells work together to form tissues and organs. In breast tissue, for example, differentiated basal cells and luminal cells combine to form milk ducts.

While analyzing cells from human breast tissue, Christine Chaffer, who is a postdoctoral researcher in the Weinberg lab and first author of the PNAS paper, observed a small number of living basal cells floating freely in the tissue culture medium.

Intrigued by the cells' unusual behavior, Chaffer conducted further targeted investigations, including injection of the floating basal cells into mice. After 12 weeks she found that the injected basal cells gave rise to milk duct-like structures containing both basal and luminal cells a clear indication that the floating cells had de-differentiated into stem-like cells.

Until now, no one has shown that differentiated mammalian cells, like these basal cells, have the ability to spontaneously revert to the stem-like state (a behavior described as plasticity).

To see if basal cells could become cancer stem cells, Chaffer inserted cancer-causing genes into the cells. When these transformed cells were injected into mice, the resulting tumors were found to include a cancer stem cell population that descended from the original injected basal (more differentiated) cells. These results indicate that basal cells in breast cancer tumors can serve as a previously unidentified source of cancer stem cells.

As research for new cancer therapies has recently focused on eliminating cancer stem cells, Weinberg cautions that the plasticity seen in these basal cells suggests a more complicated scenario than previously thought.

"Future drug therapies that are targeted against cancer will need to eliminate the cancer stem cells and, in addition, get rid of the non-stem cells in tumors both populations must be removed," says Weinberg, who is also a professor of biology at MIT. "Knocking out one or the other is unlikely to suffice to generate a durable clinical response."

Chaffer is now focusing on what actually prompts these flexible cells to de-differentiate, and in the case of cancer cells, how to stop the cells from converting into cancer stem cells.

"This plasticity can occur naturally, and it seems that the trigger may be a physiological mechanism for restoring a pool of stem cells," says Chaffer. "We believe that certain cells are more susceptible to such a trigger and therefore to conversion from a differentiated to a stem-like state, and that this process occurs more frequently in cancerous cells."

In the case of normal epithelial cells, the observed behavior may also allow patient specific adult stem cells to be derived without genetic manipulation, holding promise for degenerative disease therapy.

This research was supported by the National Health and Medical Research Council of Australia, National Institutes of Health, MIT's Ludwig Center for Molecular Oncology, the Breast Cancer Research Foundation, and a Department of Defense Breast Cancer Research Program Idea Award.

Source: Whitehead Institute for Biomedical Research

 

Dainippon Sumitomo Pharma Co., Ltd. And Boston Biomedical, Inc. Enter Strategic Partnership On Anti-Cancer Drugs Targeting Cancer Stem Cells

Dainippon Sumitomo Pharma Co., Ltd. ("DSP") and Boston Biomedical, Inc. ("BBI"), announced that they have signed a Product Option License Agreement for BBI608 for all oncology indications in Japan and exclusive right of negotiation for BBI608 for the United States and Canada.

BBI608 is an orally administered, first-in-class, small molecule anti-cancer drug that targets highly malignant cancer stem cells as well as other heterogeneous cancer cells. In clinical trials to date, BBI608 has shown excellent safety, favorable pharmacokinetics, and encouraging signs of anticancer activity. BBI608 is under phase I extension clinical studies in colorectal cancer and phase Ib/II trials in multiple solid tumor types.

Under the terms of the agreement, BBI will receive $15million of upfront payment and clinical trial support upon signing. Based on the outcome of the clinical trials, DSP has the option to acquire exclusive rights for the development and commercialization for BBI608 in Japan. In addition, DSP has an exclusive negotiation right for the United States and Canada for a certain time. During this option agreement period, DSP will pay a maximum of $55million for part of the development costs of BBI608 and for continuation of the option. Assuming DSP exercise the option for Japan, upon successful clinical development and commercialization of BBI608 in Japan, BBI could receive a maximum of approximately $100million in aggregate, including milestone payments associated with successful development and commercialization, in addition to running royalties.

Masayo Tada, President and chief executive officer of DSP, said, "DSP recognizes oncology as an area with high unmet medical needs and has already spent substantial effort, defining it as a major specialty area. We are delighted to enter into this strategic partnership with Boston Biomedical in the oncology area to develop BBI608 as a highly differentiated, novel anti-cancer drug. With the addition of BBI608 to our research pipeline, DSP hopes to raise its presence in the therapeutic area of cancer while making a contribution to treatment for cancer patients."

"We are excited to form this strategic oncology partnership with Dainippon Sumitomo Pharma on BBI608," said Chiang J. Li, Chairman and chief executive officer of BBI. "With DSP's outstanding track record in bringing innovative medicine to patients, this partnership marks not only a significant milestone for BBI as we execute our global development strategy for BBI608, but also a significant step towards translating cancer stem cell science to truly innovative therapeutics for cancer patients."

About BBI608 and Cancer Stem Cells

BBI608 is a first-in-class, cancer stem cell inhibitor, currently in clinical development. Cancer stem cells (CSCs), being refractory to current cancer therapies, represent an emerging approach for designing the next generation of oncology therapeutics. CSCs are considered to be fundamentally responsible for malignant growth, metastasis, and recurrence. These cells are a subpopulation of cancer cells that have self-renewal ability and can differentiate into the heterogeneous cancer cells that comprise the bulk of the tumor mass. CSCs have been isolated from almost every major type of cancer, and have been found to be intrinsically resistant to current cancer therapies. Targeting CSCs, therefore, holds great promise for fundamentally advancing cancer treatment.

BBI608, through its undisclosed molecular target, simultaneously inhibits multiple key cancer cell stemness pathways. BBI608 targets highly malignant CSCs as well as heterogeneous cancer cells. In clinical trials to date, BBI608 has shown excellent safety, favorable pharmacokinetics, and encouraging signs of anticancer activity against a broad range of tumor types. BBI608 is currently in phase I extension in colorectal cancer and phase Ib/II trials for combination therapy with paclitaxel for selected solid tumor types.

Source: Boston Biomedical, Inc

 

Stem Cells Implicated In The Cause Of Bowel Cancer May Also Be Useful In Treating The Disease

Editor's Choice

Stem cells in the intestine, which when they mutate can lead to bowel cancers, might also be grown into transplant tissues to combat the effects of those same cancers, the UK National Stem Cell Network (UKNSCN) annual science meeting heard.

Professor Nick Barker of the Institute of Medical Biology in Singapore will explain how he and his team identified that the stem cells which are crucial to maintaining a healthy intestine are also the site at which bowel cancers first begin, and how he also hopes to use healthy stem cells to regenerate tissues to help patients with Crohn's disease and some cancers.

Having discovered a gene that is only turned on in these particular stem cells Professor Barker and his team have been able to isolate the cells in mice and grow small pieces of intestine in the lab. The researchers hope that if they are able to grow larger pieces, they will be able to produce transplant tissues to replace damaged intestines.

Professor Barker explains: "Processing our dinner every day is a tough job so the lining of our intestines quickly get worn out. To keep the intestine working stem cells in little pockets along the surface replace the lining, cell by cell, about once a week.

"We already knew these stem cells existed for a while we didn't know much about them because it was difficult to distinguish them from all of the other types of cells in our intestines. Our team was able to single them out and study them because we discovered a gene that is only turned on in these particular stem cells."

Once the researchers had found this gene they were able to track where the stem cells occur throughout the body finding that, as well as the intestine, the stomach lining and in hair follicles, the cells were also present in bowel tumours.

Professor Barker continues: "We hope that studying these stem cells will be doubly useful: One day we hope to grow large enough pieces in the lab to form replacement tissues for transplant; and by studying the cells we will be able to find new ways to prevent them from mutating and hence leading to cancer.

"Bowel cancer is the third most common type of cancer in England and an estimated 38,000 new cases are diagnosed each year. We know these stem cells are both implicated in causing the cancer but that they also could be useful for treating disease so we hope that studying them will help us to understand how to attack the disease on two fronts.

Source: Biotechnology and Biological Sciences Research Council

Copyright: Medical News Today

Prostate Cancer Spreads To Bones By Overtaking The Home Of Blood Stem Cells

Like bad neighbors who decide to go wreck another community, prostate and breast cancer usually recur in the bone, according to a new University of Michigan study.

Now, U-M researchers believe they know why. Prostate cancer cells specifically target and eventually overrun the bone marrow niche, a specialized area for hematopoietic stem cells, which make red and white blood cells, said Russell Taichman, professor at the U-M School of Dentistry and senior author of the study.

Once in the niche, the cancer cells stay dormant and when they become active again years later, that's when tumors recur in the bone. The implication is that this may give us a window as to how dormancy and recurrence take place.

Taichman and a team of researchers looked in the bone marrow and found cancer cells and hematopoietic stem cells next to one another competing for the same place. The finding is important because it demonstrates that the bone marrow niche plays a central role in bone metastasis---cancers that spread into the bone-- giving researchers a new potential drug target.

Drugs could be developed to keep the types of cancers that likely recur in the bone from returning, Taichman said. For example, these drugs could either halt or disrupt how the cancer cells enter or behave in the niche, or keep the cancer cells from out-competing the stem cells.

Cancer cells act a lot like stem cells in that they must reproduce, so the U-M research group hypothesized that prostate cancer cells might travel to the niche during metastasis. One of the jobs of the niche is to keep hematopoietic stem cells from proliferating---which may be the case for cancer cells, as well, the researchers found.

So why does cancer recur? Say a person has a tumor and surgeons cut it out or do radiation, but it recurs in the bone marrow five years later, Taichman said. Those cancer cells had been circulating in the body well before the tumor was discovered, and one place those cancer cells hid is the niche.

"So what have the cancer cells been doing during those five years? Now we have a partial answer---they've been sitting in this place whose job it is to keep things from proliferating and growing," Taichman said.

"Our work also provides an explanation as to why current chemotherapies often fail in that once cancer cells enter the niche, most likely they stop proliferating," said Yusuke Shiozawa, lead author of the study. "The problem is that most of the drugs we use to try to treat cancer only work on cells that are proliferating."

Metastases are the most common malignant tumors involving the skeleton, and nearly 70 percent of patients with breast and prostate cancer have bone involvements. Roughly 15 percent to 30 percent of patients with lung, colon, stomach, bladder, uterus, rectum, thyroid or kidney cancer have bone lesions.

Researchers aren't quite sure how the cancer cells out-compete the stem cells in the niche. However, they do know the stem cells were displaced because when cancer cells were in the niche scientists also found evidence of immature blood stem cells in the blood stream, instead of in the marrow where they were supposed to be, Taichman said.

"Eventually the entire blood system is going to collapse," he said. "For example, the patient ultimately becomes anemic, gets infections, and has bleeding problems. We really don't know why people with prostate cancer die. They end up dying from different kinds of complications in part because the marrow is taken over by cancer."

The next step is to find out how the tumor cell gets into the niche and becomes dormant, and exactly what they do to the stem cells when they are there. Researchers also want to know if other types of cancer cells, such as breast cancer, also go to the niche.

The study, "Prostate Cancer Metastases Target the Hematopoietic Stem Cell Niche to Establish Footholds in Marrow," appears online in the Journal of Clinical Investigation.

Source: University of Michigan

 

Studies Track Protein Relevant To Stem Cells, Cancer

Last year, a research team at the University of North Carolina at Chapel Hill discovered one way the protein Tet 1 helps stem cells keep their pluripotency - the unique ability to become any cell type in the body. In two new studies, the team takes a broad look at the protein's location in the mouse genome, revealing a surprising dual function and offering the first genome-wide location of the protein and its product, 5-hydroxymethylcytosine - dubbed the "sixth base" of DNA.

UNC biochemist Yi Zhang, PhD, whose team conducted the studies, called the findings an important step in understanding the molecular mechanisms behind cell differentiation and the development of cancer. The findings appear in two recent papers, published March 30, 2011 online in Nature and in the April 1, 2011 issue of Genes & Development.

"There is no doubt that Tet proteins are relevant to cancer," said Zhang, Kenan distinguished professor of biochemistry and biophysics. Zhang is also an investigator of the Howard Hughes Medical Institute and a member of the UNC Lineberger Comprehensive Cancer Center. Tet proteins were initially discovered in leukemia as fusion proteins, which are commonly found in cancer cells, where they may function as oncoproteins.

In addition, Zhang said, "Tet is likely to be one of the important players for stem cell reprogramming." Learning to "reprogram" cells in the adult body to make them behave like stem cells has long been a goal for stem cell researchers; understanding how Tet proteins operate could help advance stem-cell based treatments.

Tet proteins are known to help stem cells stay pluripotent. Zhang's team analyzed Tet1's occupancy across the entire mouse embryonic stem cell genome. They found that the protein works by using a two-pronged approach to maintain the mouse embryonic stem cell state.

"On one hand, it silences the genes that are important for differentiation. On the other hand, it also activates pluripotency genes," said Zhang.

The team then focused its attention on the Tet1-catalyzed reaction product,5-hydroxymethylcytosine. 5-hydroxymethylcytosine is a modified version of cytosine - the "C" in the four main DNA bases, A, T, G, and C. 5-methylcytosine and 5-hydroxymethylcytosine have been called the fifth and sixth bases of DNA, but since 5-hydroxymethylcytosine was discovered only recently, scientists know little about it.

"Everybody is trying to understand what 5-hydroxymethylcytosine is doing," said Zhang. "Is it an intermediate, or is it an end product? What is its biological function?" Zhang's team mapped the distribution of 5-hydroxymethylcytosine across the genome, offering new insights to its role in development and disease.

"It's the first time we have the whole picture of where this new modification is in embryonic stem cells," said Zhang. "We found that its role in regulating transcription is complicated. It's not simply activating or repressing genes - it depends on the context."

Like much of science, the research answers some questions while raising others. "This study is just beginning," said Zhang. Although Tet1 is known to generate 5-hydroxymethylcytosine, there are places where one exists without the other. Further investigation could reveal more about the relationship between the two and whether other enzymes may play a role. In addition, scientists need to examine how Tet1 and 5-hydroxymethylcytosine function in animal models.

Notes:

Study collaborators include UNC postdoctoral researchers Ana D'Alessio, Shinsuke Ito, and Kai Xia, as well as Yi Sun and Hao Wu of the University of California, Los Angeles School of Medicine; Zhibin Wang of the Johns Hopkins School of Public Health; and Kairong Cui and Keji Zhao of the National Heart, Lung, and Blood Institute.

Source:
Les Lang
University of North Carolina School of Medicine