New Blood: Tracing the Beginnings of Hematopoietic Stem CellsResearchers uncover earliest clues yet to development of cells that produce all adult blood cells
Hematopoietic stem cells (HSCs) give rise to all other blood cell types, but their development and how their fate is determined has long remained a mystery. In a paper published online this week in Nature, researchers at the University of California, San Diego School of Medicine elaborate upon a crucial signaling pathway and the role of key proteins, which may help clear the way to generate HSCs from human pluripotent precursors, similar to advances with other kinds of tissue stem cells. 
Principal investigator David Traver, PhD, professor in the Department of Cellular and Molecular Medicine, and colleagues focused on the Notch signaling pathway, a system found in all animals and known to be critical to the generation of HSCs in vertebrates. “Notch signaling between emitting and receiving cells is key to establishing HSC fate during development,” said Traver. “What has not been known is where, when and how Notch signal transduction is mediated.”
Traver and colleagues discovered that the Notch signal is transduced into HSC precursor cells from signal emitting cells in the somite – embryologic tissues that eventually contribute to development of major body structures, such as skeleton, muscle and connective tissues – much earlier in the process than previously anticipated. 
More specifically, they found that JAM proteins, best known for helping maintain tight junctions between endothelial cells to prevent vascular leakage, were key mediators of Notch signaling. When the researchers caused loss of function in JAM proteins in a zebrafish model, Notch signaling and HSCs were also lost. When they enforced Notch signaling through other means, HSC development was rescued.
“To date, it has not been possible to generate HSCs de novo from human pluripotent precursors, like induced pluripotent stem cells,” said Traver. “This has been due in part to a lack of understanding of the complete set of factors that the embryo uses to make HSCs in vivo. It has also likely been due to not knowing in what order each required factor is needed.”
“Our studies demonstrate that Notch signaling is required much earlier than previously thought. In fact, it may be one of the earliest determinants of HSC fate. This finding strongly suggests that in vitro approaches to instruct HSC fate from induced pluripotent stem cells must focus on the Notch pathway at early time-points in the process. Our findings have also shown that JAM proteins serve as a sort of co-receptor for Notch signaling in that they are required to maintain close contact between signal-emitting and signal-receiving cells to permit strong activation of Notch in the precursors of HSCs.” 
The findings may have far-reaching implications for eventual development of hematopoietic stem cell-based therapies for diseases like leukemia and congenital blood disorders. Currently, it is not possible to create HSCs from differentiation of embryonic stem cells or induced pluripotent stem cells – pluripotent cells artificially derived from non-pluripotent cells, such as skin cells – that are being used in other therapeutic research efforts.

New Blood: Tracing the Beginnings of Hematopoietic Stem Cells
Researchers uncover earliest clues yet to development of cells that produce all adult blood cells

Hematopoietic stem cells (HSCs) give rise to all other blood cell types, but their development and how their fate is determined has long remained a mystery. In a paper published online this week in Nature, researchers at the University of California, San Diego School of Medicine elaborate upon a crucial signaling pathway and the role of key proteins, which may help clear the way to generate HSCs from human pluripotent precursors, similar to advances with other kinds of tissue stem cells. 

Principal investigator David Traver, PhD, professor in the Department of Cellular and Molecular Medicine, and colleagues focused on the Notch signaling pathway, a system found in all animals and known to be critical to the generation of HSCs in vertebrates. “Notch signaling between emitting and receiving cells is key to establishing HSC fate during development,” said Traver. “What has not been known is where, when and how Notch signal transduction is mediated.”

Traver and colleagues discovered that the Notch signal is transduced into HSC precursor cells from signal emitting cells in the somite – embryologic tissues that eventually contribute to development of major body structures, such as skeleton, muscle and connective tissues – much earlier in the process than previously anticipated. 

More specifically, they found that JAM proteins, best known for helping maintain tight junctions between endothelial cells to prevent vascular leakage, were key mediators of Notch signaling. When the researchers caused loss of function in JAM proteins in a zebrafish model, Notch signaling and HSCs were also lost. When they enforced Notch signaling through other means, HSC development was rescued.

“To date, it has not been possible to generate HSCs de novo from human pluripotent precursors, like induced pluripotent stem cells,” said Traver. “This has been due in part to a lack of understanding of the complete set of factors that the embryo uses to make HSCs in vivo. It has also likely been due to not knowing in what order each required factor is needed.”

“Our studies demonstrate that Notch signaling is required much earlier than previously thought. In fact, it may be one of the earliest determinants of HSC fate. This finding strongly suggests that in vitro approaches to instruct HSC fate from induced pluripotent stem cells must focus on the Notch pathway at early time-points in the process. Our findings have also shown that JAM proteins serve as a sort of co-receptor for Notch signaling in that they are required to maintain close contact between signal-emitting and signal-receiving cells to permit strong activation of Notch in the precursors of HSCs.” 

The findings may have far-reaching implications for eventual development of hematopoietic stem cell-based therapies for diseases like leukemia and congenital blood disorders. Currently, it is not possible to create HSCs from differentiation of embryonic stem cells or induced pluripotent stem cells – pluripotent cells artificially derived from non-pluripotent cells, such as skin cells – that are being used in other therapeutic research efforts.

A New Way To Control Tumor Growth
Almost all high-risk, poor-prognosis cancers have high infiltration of macrophages, immune system cells that promote tumor growth and metastasis by secreting growth factors required for tumor progression. 
A new study in Molecular Cancer Research by scientists at the University of California, San Diego School of Medicine shows that an emerging class of anticancer treatments known as PI-3K inhibitors degrade the HIF1 alpha protein as well as block tumor-induced angiogenesis and inhibit pro-angiogenic factors secreted by macrophages. The study may offer a potential therapy for treating deadly hypoxic tumors.
“Our study indicates that PI-3K inhibitors are excellent candidates for the treatment of cancers where macrophages promote tumor progression,” said lead author Shweta Joshi, PhD, postdoctoral researcher. “This is good news because it means that some new cancer therapies may help patients in more ways than was initially realized.”
“These HIF1 proteins are major players in driving the cancer state,” said co-author Donald Durden, MD, PhD, professor and vice chair for research in the Department of Pediatrics and research director, Division of Hematology/Oncology at the UC San Diego Moores Cancer Center.
“Hypoxic regions of tumors are characterized by an increased accumulation of macrophages which contributes to tumor angiogenesis and tumor progression. That is why our observation is so important, because it reveals an entirely new way of controlling tumor growth promoted by macrophages.”
Above image: An electron micrograph of a macrophage.

A New Way To Control Tumor Growth

Almost all high-risk, poor-prognosis cancers have high infiltration of macrophages, immune system cells that promote tumor growth and metastasis by secreting growth factors required for tumor progression. 

A new study in Molecular Cancer Research by scientists at the University of California, San Diego School of Medicine shows that an emerging class of anticancer treatments known as PI-3K inhibitors degrade the HIF1 alpha protein as well as block tumor-induced angiogenesis and inhibit pro-angiogenic factors secreted by macrophages. The study may offer a potential therapy for treating deadly hypoxic tumors.

“Our study indicates that PI-3K inhibitors are excellent candidates for the treatment of cancers where macrophages promote tumor progression,” said lead author Shweta Joshi, PhD, postdoctoral researcher. “This is good news because it means that some new cancer therapies may help patients in more ways than was initially realized.”

“These HIF1 proteins are major players in driving the cancer state,” said co-author Donald Durden, MD, PhD, professor and vice chair for research in the Department of Pediatrics and research director, Division of Hematology/Oncology at the UC San Diego Moores Cancer Center.

“Hypoxic regions of tumors are characterized by an increased accumulation of macrophages which contributes to tumor angiogenesis and tumor progression. That is why our observation is so important, because it reveals an entirely new way of controlling tumor growth promoted by macrophages.”

Above image: An electron micrograph of a macrophage.

Pictured: MRI technology was used to identify and locate a probable tumor (outlined in yellow) during a targeted prostate biopsy for a patient who had previously had multiple negative biopsies but had persistently high PSA levels. Resulting biospy confirmed presence of high-grade cancer.
Prostate Cancer Diagnosis Improves with MRI Technology UC San Diego Health System is the first to use new tool in San Diego
Oncologists at UC San Diego Moores Cancer Center are the first in San Diego to meld magnetic resonance imaging (MRI) technology with a traditional ultrasound prostate exam to create a three-dimensional map of the prostate that allows physicians to view growths that were previously undetectable.
An ultrasound machine provides an imperfect view of the prostate, resulting in an under-diagnosis of cancer, said J. Kellogg Parsons, MD, MHS, the UC San Diego Health System urologic oncologist who, along with Christopher Kane, MD, chair of the Department of Urology and Karim Kader, MD, PhD, urologic oncologist, is pioneering the new technology at Moores Cancer Center.
“With an ultrasound exam, we are typically unable to see the most suspicious areas of the prostate so we end up sampling different parts of the prostate that statistically speaking are more likely to have cancer,” said Parsons, who is also an associate professor in the Department of Urology at UC San Diego School of Medicine. “The MRI is a game-changer. It allows us to target the biopsy needles exactly where we think the cancer is located. It’s more precise.”
Armondo Lopez, a patient at Moores Cancer Center, had been given a clean bill of health using the traditional ultrasound biopsy method, but when his prostate-specific antigen (PSA) levels, a protein that is often elevated in men with prostate cancer, started to rise he began to worry. Parsons recommended a MRI-guided prostate biopsy. The new technology led to the diagnosis of an aggressive prostate cancer located in an area normally not visible using the ultrasound machine alone. The tumor was still in its early stage and treatable, said Parsons.
An early diagnosis typically improves a patient’s prognosis. In the United States, prostate cancer is the second leading cause of cancer death in men with more than 29,000 estimated deaths expected this year. The average age at the time of diagnosis is about 66.
More here

Pictured: MRI technology was used to identify and locate a probable tumor (outlined in yellow) during a targeted prostate biopsy for a patient who had previously had multiple negative biopsies but had persistently high PSA levels. Resulting biospy confirmed presence of high-grade cancer.

Prostate Cancer Diagnosis Improves with MRI Technology
UC San Diego Health System is the first to use new tool in San Diego

Oncologists at UC San Diego Moores Cancer Center are the first in San Diego to meld magnetic resonance imaging (MRI) technology with a traditional ultrasound prostate exam to create a three-dimensional map of the prostate that allows physicians to view growths that were previously undetectable.

An ultrasound machine provides an imperfect view of the prostate, resulting in an under-diagnosis of cancer, said J. Kellogg Parsons, MD, MHS, the UC San Diego Health System urologic oncologist who, along with Christopher Kane, MD, chair of the Department of Urology and Karim Kader, MD, PhD, urologic oncologist, is pioneering the new technology at Moores Cancer Center.

“With an ultrasound exam, we are typically unable to see the most suspicious areas of the prostate so we end up sampling different parts of the prostate that statistically speaking are more likely to have cancer,” said Parsons, who is also an associate professor in the Department of Urology at UC San Diego School of Medicine. “The MRI is a game-changer. It allows us to target the biopsy needles exactly where we think the cancer is located. It’s more precise.”

Armondo Lopez, a patient at Moores Cancer Center, had been given a clean bill of health using the traditional ultrasound biopsy method, but when his prostate-specific antigen (PSA) levels, a protein that is often elevated in men with prostate cancer, started to rise he began to worry. Parsons recommended a MRI-guided prostate biopsy. The new technology led to the diagnosis of an aggressive prostate cancer located in an area normally not visible using the ultrasound machine alone. The tumor was still in its early stage and treatable, said Parsons.

An early diagnosis typically improves a patient’s prognosis. In the United States, prostate cancer is the second leading cause of cancer death in men with more than 29,000 estimated deaths expected this year. The average age at the time of diagnosis is about 66.

More here

Adipose for a picture
Adiposity on a grand scale is a familiar sight. It describes more than one-third of American adults, categorized by the U.S. Centers for Disease Control and Prevention as obese.
Turns out that fat on the microscopic scale isn’t any more attractive, at least not these adipocytes (fat cells) captured in an electron micrograph by Steve Gschmeissner.

Adipose for a picture

Adiposity on a grand scale is a familiar sight. It describes more than one-third of American adults, categorized by the U.S. Centers for Disease Control and Prevention as obese.

Turns out that fat on the microscopic scale isn’t any more attractive, at least not these adipocytes (fat cells) captured in an electron micrograph by Steve Gschmeissner.

Novel Study Maps Infant Brain Growth In First Three Months of Life Using MRI TechnologyResults may be key in identifying and treating earliest signs of neurodevelopmental disordersA recent study conducted by researchers at the University of California, San Diego School of Medicine and the University of Hawaii demonstrates a new approach to measuring early brain development of infants, resulting in more accurate whole brain growth charts and providing the first estimates for growth trajectories of subcortical areas during the first three months after birth. Assessing the size, asymmetry and rate of growth of different brain regions could be key in detecting and treating the earliest signs of neurodevelopmental disorders, such as autism or perinatal brain injury.
The study will be published in JAMA Neurology on August 11.
For the first time, researchers used magnetic resonance imaging (MRI) of the newborn brain to calculate the volume of multiple brain regions and to map out regional growth trajectories during the infant’s first 90 days of life. The study followed the brain growth of full term and premature babies with no neurological or major health issues.
“A better understanding of when and how neurodevelopmental disorders arise in the postnatal period may help assist in therapeutic development, while being able to quantify related changes in structure size would likely facilitate monitoring response to therapeutic intervention. Early intervention during a period of high neuroplasticity could mitigate the severity of the disorders in later years,” said Dominic Holland, PhD, first author of the study and researcher in the Department of Neurosciences at UC San Diego School of Medicine.
For more than two centuries, clinicians have tracked brain growth by measuring the outside of the infant’s head with a measuring tape. The results are then plotted on a percentile chart to indicate if normal growth patterns exist. While the measurement is helpful for observing growth, it does not reveal if the individual structures within the brain are developing normally.
On average, researchers found the newborn brain grows one percent each day immediately following birth but slows to 0.4 percent per day by three months. In general for both sexes, the cerebellum, which is involved in motor control, grew at the highest rate, more than doubling volume in 90 days. The hippocampus grew at the slowest rate, increasing in volume by only 47 percent in 90 days, suggesting that the development of episodic memory is not as important at this stage of life.
“We found that being born a week premature, for example, resulted in a brain four to five percent smaller than expected for a full term baby. The brains of premature babies actually grow faster than those of term-born babies, but that’s because they’re effectively younger – and younger means faster growth,” said Holland.  “At 90 days post-delivery, however, premature brains were still two percent smaller. The brain’s rapid growth rates near birth suggest that inducing early labor, if not clinically warranted, may have a negative effect on the infant’s neurodevelopment.”
The study also found that many asymmetries in the brain are already established in the early postnatal period, including the right hippocampus being larger than the left, which historically, has been suggested to occur in the early adolescent years. Cerebral asymmetry is associated with functions such as dexterity and language abilities.
Next steps involve continuing to make advances in the application of different MRI modalities to examine the newborn brain. MRI provides high quality images of different types of tissue and does not involve radiation, like computed tomography (CT). Future research will investigate how brain structure sizes at birth and subsequent growth rates are altered as a result of alcohol and drug consumption during pregnancy.
“Our findings give us a deeper understanding of the relationship between brain structure and function when both are developing rapidly during the most dynamic postnatal growth phase for the human brain,” said Holland.
Image courtesy of NMMG

Novel Study Maps Infant Brain Growth In First Three Months of Life Using MRI Technology
Results may be key in identifying and treating earliest signs of neurodevelopmental disorders

A recent study conducted by researchers at the University of California, San Diego School of Medicine and the University of Hawaii demonstrates a new approach to measuring early brain development of infants, resulting in more accurate whole brain growth charts and providing the first estimates for growth trajectories of subcortical areas during the first three months after birth. Assessing the size, asymmetry and rate of growth of different brain regions could be key in detecting and treating the earliest signs of neurodevelopmental disorders, such as autism or perinatal brain injury.

The study will be published in JAMA Neurology on August 11.

For the first time, researchers used magnetic resonance imaging (MRI) of the newborn brain to calculate the volume of multiple brain regions and to map out regional growth trajectories during the infant’s first 90 days of life. The study followed the brain growth of full term and premature babies with no neurological or major health issues.

“A better understanding of when and how neurodevelopmental disorders arise in the postnatal period may help assist in therapeutic development, while being able to quantify related changes in structure size would likely facilitate monitoring response to therapeutic intervention. Early intervention during a period of high neuroplasticity could mitigate the severity of the disorders in later years,” said Dominic Holland, PhD, first author of the study and researcher in the Department of Neurosciences at UC San Diego School of Medicine.

For more than two centuries, clinicians have tracked brain growth by measuring the outside of the infant’s head with a measuring tape. The results are then plotted on a percentile chart to indicate if normal growth patterns exist. While the measurement is helpful for observing growth, it does not reveal if the individual structures within the brain are developing normally.

On average, researchers found the newborn brain grows one percent each day immediately following birth but slows to 0.4 percent per day by three months. In general for both sexes, the cerebellum, which is involved in motor control, grew at the highest rate, more than doubling volume in 90 days. The hippocampus grew at the slowest rate, increasing in volume by only 47 percent in 90 days, suggesting that the development of episodic memory is not as important at this stage of life.

“We found that being born a week premature, for example, resulted in a brain four to five percent smaller than expected for a full term baby. The brains of premature babies actually grow faster than those of term-born babies, but that’s because they’re effectively younger – and younger means faster growth,” said Holland.  “At 90 days post-delivery, however, premature brains were still two percent smaller. The brain’s rapid growth rates near birth suggest that inducing early labor, if not clinically warranted, may have a negative effect on the infant’s neurodevelopment.”

The study also found that many asymmetries in the brain are already established in the early postnatal period, including the right hippocampus being larger than the left, which historically, has been suggested to occur in the early adolescent years. Cerebral asymmetry is associated with functions such as dexterity and language abilities.

Next steps involve continuing to make advances in the application of different MRI modalities to examine the newborn brain. MRI provides high quality images of different types of tissue and does not involve radiation, like computed tomography (CT). Future research will investigate how brain structure sizes at birth and subsequent growth rates are altered as a result of alcohol and drug consumption during pregnancy.

“Our findings give us a deeper understanding of the relationship between brain structure and function when both are developing rapidly during the most dynamic postnatal growth phase for the human brain,” said Holland.

Image courtesy of NMMG

Clinical Trial Evaluates Safety of Stem Cell Transplantation in Spine

Researchers at the University of California, San Diego School of Medicine have launched a clinical trial to investigate the safety of neural stem cell transplantation in patients with chronic spinal cord injuries. This Phase I clinical trial is recruiting eight patients for the 5-year study.

“The goal of this study is to evaluate the safety of transplanting neural stem cells into the spine for what one day could be a treatment for spinal cord injuries,” said Joseph Ciacci, MD, principal investigator and neurosurgeon at UC San Diego Health System. “The study’s immediate goal, however, is to determine whether  injecting these neural stem cells into the spine of patients with spinal cord injury is safe.”

Related goals of the clinical trial include evaluating the stem cell graft’s survival and the effectiveness of immunosuppression drugs to prevent rejection. The researchers will also look for possible therapeutic benefits such as changes in motor and sensory function, bowel and bladder function, and pain levels.

Patients who are accepted for the study will have spinal cord injury to the T7-T12 level of the spine’s vertebrae and will have incurred their injury between one and two years ago.

All participants will receive the stem cell injection. The scientists will use a line of human stem cells approved by the U.S. FDA for human trials in patients with chronic traumatic spinal injuries.  These cells were previously tested for safety in patients with amyotrophic lateral sclerosis (ALS).

Since stem cell transplantation for spinal cord injury is just beginning clinical tests, unforeseen risks, complications or unpredictable outcomes are possible. Careful clinical testing is essential to ensure that this type of therapy is developed responsibly with appropriate management of the risks that all medical therapies may present.

Pre-clinical studies of these cells by Ciacci and Martin Marsala, MD, at the UC San Diego School of Medicine, showed that these grafted neural stem cells improved motor function in spinal cord injured rats with minimal side effects indicating that human clinical trials are now warranted.

This clinical trial at UC San Diego Health System is funded by Neuralstem, Inc. and was launched and supported by the UC San Diego Sanford Stem Cell Clinical Center. The Center was recently created to advance leading-edge stem cell medicine and science, protect and counsel patients, and accelerate innovative stem cell research into patient diagnostics and therapy.

To learn more about eligibility for this clinical trial, please call Amber Faulise at 858-657-5175 or email her at rfaulise@ucsd.edu

How Breast Cancer Usurps the Powers of Mammary Stem Cells
During pregnancy, certain hormones trigger specialized mammary stem cells to create milk-producing cells essential to lactation. Scientists at the University of California, San Diego School of Medicine and Moores Cancer Center have found that mammary stem cells associated with the pregnant mammary gland are related to stem cells found in breast cancer. 
Writing in the August 11, 2014 issue of Developmental Cell, David A. Cheresh, PhD, Distinguished Professor of Pathology and vice-chair for research and development, Jay Desgrosellier, PhD, assistant professor of pathology and colleagues specifically identified a key molecular pathway associated with aggressive breast cancers that is also required for mammary stem cells to promote lactation development during pregnancy. 
“By understanding a fundamental mechanism of mammary gland development during pregnancy, we have gained a rare insight into how aggressive breast cancer might be treated,” said Cheresh. “This pathway can be exploited. Certain drugs are known to disrupt this pathway and may interfere with the process of breast cancer progression.”
During pregnancy, a new mammary stem cell population arises, distinct from those involved in development and maintenance of the non-pregnant gland. These stem cells remodel the breasts and lactating glands in preparation for feeding the newborn child. Normally, these stem cells contribute only to early remodeling events and are switched off by the time milk production begins.
The researchers found, however, that signals regulating stem cell activation during pregnancy appear to be hijacked by cancer cells to produce faster-growing, more aggressive tumors. “This normal pathway ends up contributing to the progression of cancer,” said Desgrosellier, first author of the study.
A connection between pregnancy and breast cancer has long been known. But the association between pregnancy and breast cancer risk is complex. While having a child reduces a woman’s risk of developing breast cancer later in life, there is also an increased short-term risk for the development of a highly aggressive form of breast cancer following each pregnancy. The current study suggests that molecules important for stem cell behavior during pregnancy may contribute to these more aggressive pregnancy-associated breast cancers, a possibility the researchers plan to investigate further.
The authors are quick to point out that their findings should not be interpreted as a reason to avoid pregnancy. The signaling pathway usurped by cancer cells is not the cause of breast cancer. Rather, they said, it may worsen or accelerate a cancer caused by other factors, such as an underlying mutation or genetic predisposition.
“Our work doesn’t speak to the actual cause of cancer. Rather, it explains what can happen once cancer has been initiated,” said Cheresh. “Here’s an analogy: To get cancer, you first have to start with an oncogene, a gene that carries a mutation and has the potential to initiate cancer. Think of the oncogene as turning on a car’s ignition. The signaling pathway exploited by cancer cells is like applying gas. It gets the car moving, but it means nothing if the oncogene hasn’t first started the process.”
The researchers focused on a family of cell surface receptor proteins called integrins that act as key communications conduits, ultimately zeroing in on the role of one member of this family called beta-3 integrin. Also known as CD61, it was already linked to metastasis and resistance to cancer drugs.
Cheresh noted that CD61 represents a good marker for the incriminated signaling pathway involved in both mammary development during pregnancy and cancer. It’s easily detected and could be used to both diagnose and treat breast cancer cases. “Detecting CD61 might help doctors determine what kind of therapeutic approach to use, knowing that they might be dealing with a more aggressive yet treatable form of breast cancer. For example, there are existing drugs that block CD61 signaling, which might be another potential aspect of treatment.”

How Breast Cancer Usurps the Powers of Mammary Stem Cells

During pregnancy, certain hormones trigger specialized mammary stem cells to create milk-producing cells essential to lactation. Scientists at the University of California, San Diego School of Medicine and Moores Cancer Center have found that mammary stem cells associated with the pregnant mammary gland are related to stem cells found in breast cancer. 

Writing in the August 11, 2014 issue of Developmental Cell, David A. Cheresh, PhD, Distinguished Professor of Pathology and vice-chair for research and development, Jay Desgrosellier, PhD, assistant professor of pathology and colleagues specifically identified a key molecular pathway associated with aggressive breast cancers that is also required for mammary stem cells to promote lactation development during pregnancy. 

“By understanding a fundamental mechanism of mammary gland development during pregnancy, we have gained a rare insight into how aggressive breast cancer might be treated,” said Cheresh. “This pathway can be exploited. Certain drugs are known to disrupt this pathway and may interfere with the process of breast cancer progression.”

During pregnancy, a new mammary stem cell population arises, distinct from those involved in development and maintenance of the non-pregnant gland. These stem cells remodel the breasts and lactating glands in preparation for feeding the newborn child. Normally, these stem cells contribute only to early remodeling events and are switched off by the time milk production begins.

The researchers found, however, that signals regulating stem cell activation during pregnancy appear to be hijacked by cancer cells to produce faster-growing, more aggressive tumors. “This normal pathway ends up contributing to the progression of cancer,” said Desgrosellier, first author of the study.

A connection between pregnancy and breast cancer has long been known. But the association between pregnancy and breast cancer risk is complex. While having a child reduces a woman’s risk of developing breast cancer later in life, there is also an increased short-term risk for the development of a highly aggressive form of breast cancer following each pregnancy. The current study suggests that molecules important for stem cell behavior during pregnancy may contribute to these more aggressive pregnancy-associated breast cancers, a possibility the researchers plan to investigate further.

The authors are quick to point out that their findings should not be interpreted as a reason to avoid pregnancy. The signaling pathway usurped by cancer cells is not the cause of breast cancer. Rather, they said, it may worsen or accelerate a cancer caused by other factors, such as an underlying mutation or genetic predisposition.

“Our work doesn’t speak to the actual cause of cancer. Rather, it explains what can happen once cancer has been initiated,” said Cheresh. “Here’s an analogy: To get cancer, you first have to start with an oncogene, a gene that carries a mutation and has the potential to initiate cancer. Think of the oncogene as turning on a car’s ignition. The signaling pathway exploited by cancer cells is like applying gas. It gets the car moving, but it means nothing if the oncogene hasn’t first started the process.”

The researchers focused on a family of cell surface receptor proteins called integrins that act as key communications conduits, ultimately zeroing in on the role of one member of this family called beta-3 integrin. Also known as CD61, it was already linked to metastasis and resistance to cancer drugs.

Cheresh noted that CD61 represents a good marker for the incriminated signaling pathway involved in both mammary development during pregnancy and cancer. It’s easily detected and could be used to both diagnose and treat breast cancer cases. “Detecting CD61 might help doctors determine what kind of therapeutic approach to use, knowing that they might be dealing with a more aggressive yet treatable form of breast cancer. For example, there are existing drugs that block CD61 signaling, which might be another potential aspect of treatment.”

Dramatic Growth of Grafted Stem Cells in Rat Spinal Cord InjuriesReprogrammed human neurons extend axons almost entire length of central nervous system
Building upon previous research, scientists at the University of California, San Diego School of Medicine and Veteran’s Affairs San Diego Healthcare System report that neurons derived from human induced pluripotent stem cells (iPSC) and grafted into rats after a spinal cord injury produced cells with tens of thousands of axons extending virtually the entire length of the animals’ central nervous system.
Writing in the August 7 early online edition of Neuron, lead scientist Paul Lu, PhD, of the UC San Diego Department of Neurosciences and colleagues said the human iPSC-derived axons extended through the white matter of the injury sites, frequently penetrating adjacent gray matter to form synapses with rat neurons. Similarly, rat motor axons pierced the human iPSC grafts to form their own synapses. 
The iPSCs used were developed from a healthy 86-year-old human male.
“These findings indicate that intrinsic neuronal mechanisms readily overcome the barriers created by a spinal cord injury to extend many axons over very long distances, and that these capabilities persist even in neurons reprogrammed from very aged human cells,” said senior author Mark Tuszynski, MD, PhD, professor of Neurosciences and director of the UC San Diego Center for Neural Repair.
For several years, Tuszynski and colleagues have been steadily chipping away at the notion that a spinal cord injury necessarily results in permanent dysfunction and paralysis. Earlier work has shown that grafted stem cells reprogrammed to become neurons can, in fact, form new, functional circuits across an injury site, with the treated animals experiencing some restored ability to move affected limbs. The new findings underscore the potential of iPSC-based therapy and suggest a host of new studies and questions to be asked, such as whether axons can be guided and how will they develop, function and mature over longer periods of time.
While neural stem cell therapies are already advancing to clinical trials, this research raises cautionary notes about moving to human therapy too quickly, said Tuszynski.
“The enormous outgrowth of axons to many regions of the spinal cord and even deeply into the brain raises questions of possible harmful side effects if axons are mistargeted. We also need to learn if the new connections formed by axons are stable over time, and if implanted human neural stem cells are maturing on a human time frame – months to years – or more rapidly. If maturity is reached on a human time frame, it could take months to years to observe functional benefits or problems in human clinical trials.”
In the latest work, Lu, Tuszynski and colleagues converted skin cells from a healthy 86-year-old man into iPSCs, which possess the ability to become almost any kind of cell. The iPSCs were then reprogrammed to become neurons in collaboration with the laboratory of Larry Goldstein, PhD, director of the UC San Diego Sanford Stem Cell Clinical Center. The new human neurons were subsequently embedded in a matrix containing growth factors and grafted into two-week-old spinal cord injuries in rats.
Three months later, researchers examined the post-transplantation injury sites. They found biomarkers indicating the presence of mature neurons and extensive axonal growth across long distances in the rats’ spinal cords, even extending into the brain. The axons traversed wound tissues to penetrate and connect with existing rat neurons. Similarly, rat neurons extended axons into the grafted material and cells. The transplants produced no detectable tumors.
While numerous connections were formed between the implanted human cells and rat cells, functional recovery was not found. However, Lu noted that tests assessed the rats’ skilled use of the hand. Simpler assays of leg movement could still show benefit. Also, several iPSC grafts contained scars that may have blocked beneficial effects of new connections. Continuing research seeks to optimize transplantation methods to eliminate scar formation.
Tuszynski said he and his team are attempting to identify the most promising neural stem cell type for repairing spinal cord injuries. They are testing iPSCs, embryonic stem cell-derived cells and other stem cell types.
“Ninety-five percent of human clinical trials fail. We are trying to do as much as we possibly can to identify the best way of translating neural stem cell therapies for spinal cord injury to patients. It’s easy to forge ahead with incomplete information, but the risk of doing so is greater likelihood of another failed clinical trial. We want to determine as best we can the optimal cell type and best method for human translation so that we can move ahead rationally and, with some luck, successfully.”
Pictured: Image depicts extension of human axons into host adult rat white matter and gray matter three months after spinal cord injury and transplantation of human induced pluripotent stem cell-derived neurons. Green fluorescent protein identifies human graft-derived axons, myelin (red) indicates host rat spinal cord white matter and blue marks host rat gray matter.

Dramatic Growth of Grafted Stem Cells in Rat Spinal Cord Injuries
Reprogrammed human neurons extend axons almost entire length of central nervous system

Building upon previous research, scientists at the University of California, San Diego School of Medicine and Veteran’s Affairs San Diego Healthcare System report that neurons derived from human induced pluripotent stem cells (iPSC) and grafted into rats after a spinal cord injury produced cells with tens of thousands of axons extending virtually the entire length of the animals’ central nervous system.

Writing in the August 7 early online edition of Neuron, lead scientist Paul Lu, PhD, of the UC San Diego Department of Neurosciences and colleagues said the human iPSC-derived axons extended through the white matter of the injury sites, frequently penetrating adjacent gray matter to form synapses with rat neurons. Similarly, rat motor axons pierced the human iPSC grafts to form their own synapses. 

The iPSCs used were developed from a healthy 86-year-old human male.

“These findings indicate that intrinsic neuronal mechanisms readily overcome the barriers created by a spinal cord injury to extend many axons over very long distances, and that these capabilities persist even in neurons reprogrammed from very aged human cells,” said senior author Mark Tuszynski, MD, PhD, professor of Neurosciences and director of the UC San Diego Center for Neural Repair.

For several years, Tuszynski and colleagues have been steadily chipping away at the notion that a spinal cord injury necessarily results in permanent dysfunction and paralysis. Earlier work has shown that grafted stem cells reprogrammed to become neurons can, in fact, form new, functional circuits across an injury site, with the treated animals experiencing some restored ability to move affected limbs. The new findings underscore the potential of iPSC-based therapy and suggest a host of new studies and questions to be asked, such as whether axons can be guided and how will they develop, function and mature over longer periods of time.

While neural stem cell therapies are already advancing to clinical trials, this research raises cautionary notes about moving to human therapy too quickly, said Tuszynski.

“The enormous outgrowth of axons to many regions of the spinal cord and even deeply into the brain raises questions of possible harmful side effects if axons are mistargeted. We also need to learn if the new connections formed by axons are stable over time, and if implanted human neural stem cells are maturing on a human time frame – months to years – or more rapidly. If maturity is reached on a human time frame, it could take months to years to observe functional benefits or problems in human clinical trials.”

In the latest work, Lu, Tuszynski and colleagues converted skin cells from a healthy 86-year-old man into iPSCs, which possess the ability to become almost any kind of cell. The iPSCs were then reprogrammed to become neurons in collaboration with the laboratory of Larry Goldstein, PhD, director of the UC San Diego Sanford Stem Cell Clinical Center. The new human neurons were subsequently embedded in a matrix containing growth factors and grafted into two-week-old spinal cord injuries in rats.

Three months later, researchers examined the post-transplantation injury sites. They found biomarkers indicating the presence of mature neurons and extensive axonal growth across long distances in the rats’ spinal cords, even extending into the brain. The axons traversed wound tissues to penetrate and connect with existing rat neurons. Similarly, rat neurons extended axons into the grafted material and cells. The transplants produced no detectable tumors.

While numerous connections were formed between the implanted human cells and rat cells, functional recovery was not found. However, Lu noted that tests assessed the rats’ skilled use of the hand. Simpler assays of leg movement could still show benefit. Also, several iPSC grafts contained scars that may have blocked beneficial effects of new connections. Continuing research seeks to optimize transplantation methods to eliminate scar formation.

Tuszynski said he and his team are attempting to identify the most promising neural stem cell type for repairing spinal cord injuries. They are testing iPSCs, embryonic stem cell-derived cells and other stem cell types.

“Ninety-five percent of human clinical trials fail. We are trying to do as much as we possibly can to identify the best way of translating neural stem cell therapies for spinal cord injury to patients. It’s easy to forge ahead with incomplete information, but the risk of doing so is greater likelihood of another failed clinical trial. We want to determine as best we can the optimal cell type and best method for human translation so that we can move ahead rationally and, with some luck, successfully.”

Pictured: Image depicts extension of human axons into host adult rat white matter and gray matter three months after spinal cord injury and transplantation of human induced pluripotent stem cell-derived neurons. Green fluorescent protein identifies human graft-derived axons, myelin (red) indicates host rat spinal cord white matter and blue marks host rat gray matter.

Hey, remember this post? Learn more about how a diet high in capsaicin may (or may not) lower your risk of colorectal cancer on our sister blog!
ucsdcancer:

Photo credit: “Chili (633442211)” by Randi Hausken from Bærum, Norway - Chili Uploaded by russavia. Licensed under Creative Commons Attribution-Share Alike 2.0 via Wikimedia Commons 

Food for thought: Chili peppers are more than spice in your diet
Attend one of our free Healing Foods Kitchen cooking classes and you’ll hear Susan Faerber tell you that capsaicin, the active ingredient that makes chili peppers hot, has protective benefits against cancer. In a study published in the Aug. 1 issue of The Journal of Clinical Investigation, UC San Diego Moores Cancer Center researchers say capsaicin triggers a reaction that reduces the risk of colorectal tumors.
But before you add a Carolina Reaper, the world’s hottest pepper, to one of Susan’s cancer fighting recipes or your own healthy meal, read about the science behind the study at our sister blog ucsdhealthsciences.
We asked the researchers to break down this spicy news for our own consumption and tell us what does it mean for you and me? Do countries with a traditionally high use of chili peppers in their diet see lower incidence of colorectal cancer?
The answer is a bit complicated and we must be cautious to infer any cause-and-effect relationships from epidemiological data, said Petrus de Jong, MD, first author of the study. Still, a 2009 study on colorectal cancer incidence shows there are benefits.
“Countries with a high dietary intake of capsaicinoids (e.g. India, Bangladesh, Thailand, Mexico) show a five to 10-fold lower incidence of colorectal cancer compared to Western countries,” said Dr. de Jong.
“Various factors may be associated with the reduced incidence of colorectal cancer in these countries, including dietary factors such as low consumption of red meats and high consumption of non-starch polysaccharides, vegetables and phytochemicals (i.e. capsaicin). Indeed, a shift from a traditional Mexican to a predominantly Western diet has been associated with an increased risk of this cancer as shown by a 2003 study.”
So there is a benefit! But, how much do we need to eat?
“A significant anti-tumor effect would require more than just ‘a spicy diet’,” said Dr. de Jong.
The amount of capsaicin used in the experiments is at least five times higher than what the average people in countries who eat lots chili pepper consume. Dr. de Jong says a good starting point to determine how much capsaicin we need to ingest would be a feasibility study that would target the active substance mainly to the large intestine. So until then, eat your habanero, jalapeño, piri piri or the pepper of choice depending on your heat level tolerance and know that it has some health benefits in addition to adding flavor to your meals.
Bon appétit. 

Hey, remember this post? Learn more about how a diet high in capsaicin may (or may not) lower your risk of colorectal cancer on our sister blog!

ucsdcancer:

Photo credit: “Chili (633442211)” by Randi Hausken from Bærum, Norway - Chili Uploaded by russavia. Licensed under Creative Commons Attribution-Share Alike 2.0 via Wikimedia Commons

Food for thought: Chili peppers are more than spice in your diet

Attend one of our free Healing Foods Kitchen cooking classes and you’ll hear Susan Faerber tell you that capsaicin, the active ingredient that makes chili peppers hot, has protective benefits against cancer. In a study published in the Aug. 1 issue of The Journal of Clinical Investigation, UC San Diego Moores Cancer Center researchers say capsaicin triggers a reaction that reduces the risk of colorectal tumors.

But before you add a Carolina Reaper, the world’s hottest pepper, to one of Susan’s cancer fighting recipes or your own healthy meal, read about the science behind the study at our sister blog ucsdhealthsciences.

We asked the researchers to break down this spicy news for our own consumption and tell us what does it mean for you and me? Do countries with a traditionally high use of chili peppers in their diet see lower incidence of colorectal cancer?

The answer is a bit complicated and we must be cautious to infer any cause-and-effect relationships from epidemiological data, said Petrus de Jong, MD, first author of the study. Still, a 2009 study on colorectal cancer incidence shows there are benefits.

“Countries with a high dietary intake of capsaicinoids (e.g. India, Bangladesh, Thailand, Mexico) show a five to 10-fold lower incidence of colorectal cancer compared to Western countries,” said Dr. de Jong.

“Various factors may be associated with the reduced incidence of colorectal cancer in these countries, including dietary factors such as low consumption of red meats and high consumption of non-starch polysaccharides, vegetables and phytochemicals (i.e. capsaicin). Indeed, a shift from a traditional Mexican to a predominantly Western diet has been associated with an increased risk of this cancer as shown by a 2003 study.”

So there is a benefit! But, how much do we need to eat?

“A significant anti-tumor effect would require more than just ‘a spicy diet’,” said Dr. de Jong.

The amount of capsaicin used in the experiments is at least five times higher than what the average people in countries who eat lots chili pepper consume. Dr. de Jong says a good starting point to determine how much capsaicin we need to ingest would be a feasibility study that would target the active substance mainly to the large intestine. So until then, eat your habanero, jalapeño, piri piri or the pepper of choice depending on your heat level tolerance and know that it has some health benefits in addition to adding flavor to your meals.

Bon appétit. 

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