This new idea also explains why so many cancer patients say that “their cancer is eating them alive” – an accurate observation that has never been understood, the researchers say.
 

These four new studies, co-published in the September issue of the journal Cell Cycle, provide evidence that tumor growth and metastasis is directly “fueled” by normal supporting cells.

These supporting cells are called fibroblasts (fibroblast: A cell that gives rise to connective tissue) and they produce the stroma (connective tissue) (Stroma: the connective, functionally supportive framework of a biological cell, tissue, or organ) that surrounds tumor cells. As the cancer progresses, increasing numbers of these stromal cells eat themselves to provide recycled nutrients to tumor cells – leading to dramatic weight loss in patients.

They also found that without recycled nutrients provided by fibroblasts, tumor cells are more fragile and die. Based on this breakthrough, the researchers propose that available drugs (now on the market), which sever the “parasitic” connection between tumor cells and fibroblasts, may be effective therapeutics.

“We think we have finally figured out how cancer really works – and this reverses 85 years of dogma, upon which current cancer research and therapy is based,” says the study’s senior investigator, Michael P. Lisanti, M.D., Ph.D., Chairman of Jefferson’s Department of Stem Cell Biology & Regenerative Medicine.

The prevailing theory, known as the Warburg Effect, developed by German researcher Otto Warburg in 1924 (for which he won a Nobel prize), says that tumor cells change their metabolism in order to fuel their own growth. As evidence, Warburg pointed to a lack of mitochondria, which are tiny “power plants,” in laboratory cancer cells, saying these cells have found another way to produce the energy they need.

Richard Pestell, MB, BS, MD, Ph.D, FRACP, director of the Kimmel Cancer Center and co-author on these studies notes, “These studies suggest that the absence of mitochondria in laboratory cancer cells may reflect in part that cultured cells have had to adjust to life outside of their original environment, without their stromal partner.” Drs. Lisanti, Pestell and colleagues found this out by performing a simple experiment in which they mixed cancer cells and fibroblasts together, and then searched for mitochondria. The found the fibroblasts didn’t have any mitochondria, and that the cancer cells had all the mitochondria.

“The Warburg Effect is happening, but it is happening to fibroblasts, not to cancer cells. Fibroblasts have no mitochondria because they are eating them to provide energy to cancer cells, and cancer cells have a ton of mitochondria because they need these power plants to process all the recycled nutrients given to them by fibroblasts, which then helps them grow and spread,” Dr. Lisanti says.

They have dubbed this finding “The Reverse Warburg Effect.”

“It’s amazing,” Dr. Lisanti says. “Much of what we know about cancer is backwards because cancer researchers used isolated tumor cells for most cancer studies. Now, when we put cancer cells back in their stromal environment, we see how cancer cells critically depend on fibroblasts for their survival.”

Tumor cells do this by employing oxidative stress as a weapon. Then, oxidative stress in fibroblasts “tricks” these stromal cells into eating themselves to feed cancer cells, the researchers say. This process of “self-eating” or “self-cannibalism” is called autophagy.

During periods of starvation, normal cells undergo autophagy. This metabolic re-programming allows cells to recycle nutrients by continually eating themselves, including their mitochondria. This permits starving cells to recycle nutrients and to survive under hostile conditions.

Now, Dr. Lisanti and colleagues have figured out how cancer cells take advantage of this recycling process. To satisfy their large appetite, hungry cancer cells induce oxidative stress in the fibroblasts and this stress forces the stromal cells to eat themselves, which provides recycled nutrients or “food” to fuel survival of nearby cancer cells.

“It’s that simple. Cancer cells are eating us alive by stealing nutrients from normal cells using oxidative stress, and by employing those recycled nutrients to support their own growth. Stem cells are then recruited from the bone marrow to produce fresh fibroblasts, to continually fuel cancer cell growth,” Dr. Lisanti says. “For years, cancer patients have said they felt as though the cancer in their body was eating them alive. These patients were right. Essentially, the cancer knows how to induce oxidative stress and turns a local wasting process into a whole-body phenomenon.”

Co-author Ubaldo Martinez-Outschoorn, M.D., a medical oncologist at Jefferson says “Patients have been telling us that cancer is eating them alive for years: Now we know they were right!” One of his cancer patients recently said, “Doc, I can’t eat enough food to maintain my weight. No matter how much I eat, I feel tired, and I am always losing weight.”

“Now that we understand the mechanism, this reverses our thinking about cancer metabolism and about how to stop this stress and starve the cancer cells,” he says.

In one of the published studies, Dr. Lisanti shows that using anti-oxidants can prevent oxidative stress in the fibroblasts, thus cutting off the fuel supply to cancer cells, starving them. “We are now performing drug screening assays to discover new anti-oxidants and other molecules like this,” he says.

The researchers have additionally identified two key metabolites – ketones and lactate – produced by the co-opted fibroblasts that provide high-energy food to the cancer cells. This finding also explains a mystery and provides a warning.

The mystery concerns why people with diabetes are much more likely to develop cancer than non-diabetics. The reason, Dr. Lisanti says, is that diabetic patients produce elevated levels of ketones, and he now shows that ketones fuel cancer cell growth.
The warning comes from the common use of lactate, a type of sugar, in cancer patients. Surgeons often give their cancer patients an intravenous solution of lactate before, during, and after surgery, Dr. Lisanti says. “But we see that cancer cells are using energy-rich fuels, such as lactate, to increase their numbers of mitochondria to power cancer cell growth, survival, and metastasis, so surgeons may want to re-consider or stop this practice.”

The findings have led the researchers to question the value of research using isolated laboratory cancer cells – the basis of most cancer research – and the anticancer drugs that result from it.

For example, genetic mutations have long been thought to be the root cause of cancer, but Dr. Lisanti’s group observed that these alterations might be the consequence of the tumor cell’s interactions with the normal stroma. Oxidative stress induced by cancer cells in fibroblasts feeds back upon cancer cells, amplifying the production of reactive oxygen species (ROS). They believe that ROS is then used by cancer cells to mutate their own genes to promote survival.

“These ROS molecules cause DNA damage in the cancer cells, resulting in genomic instability – random mutations and DNA breakage, as well as abnormal chromosome numbers. This instability helps cancer cells evolve into a more aggressive form,” Dr. Lisanti says.

“So, we see three consequences resulting from activating oxidative stress in normal stromal cells,” he says. “First, it forces stromal cells to make food for cancer cells. Second, this abundance of food protects the cancer cells against death. Finally, oxidative stress modifies cancer cell DNA, causing mutations and allowing them to evolve into a more aggressive form.”

Additionally, the researchers say their new theory of stromal metabolic re-programming suggests that cancer cells do not need blood vessels to feed them, which explains why some angiogensis inhibitors (drugs that shut down blood vessel growth) have not worked – and, in fact, may be dangerous.

“If an aggressive cancer cell can use oxidative stress to extract nutrients from normal stromal cells, it can go anywhere without the need for a blood supply. This may be how cancer cells spread all over the body,” Dr. Lisanti says. “Furthermore, angiogenesis inhibitors induce hypoxia, which is low oxygen, in the stroma. This is exactly the condition that drives nutrient recycling via autophagy. So angiogenesis inhibitors may help provide food or recycled nutrients to feed cancer cells. This explains why angiogenesis inhibitors have been very disappointing in clinical trials, as they may be having just the opposite effect, promoting cancer cell growth and metastasis.”

These new findings also have clear implications for cancer diagnosis, the researchers say. Many of the molecules that Dr. Lisanti’s group identified could be used as diagnostics to identify high-risk cancer patients or to monitor the success of their anti-cancer therapy.

Among them is caveolin-1 (Cav-1), which is produced by fibroblasts. Dr. Lisanti had shown earlier that loss of Cav-1 predicts poor prognosis in breast cancer patients, and is linked to early tumor recurrence, metastasis, and drug resistance. He now understands why, as breast cancer patients with absent stromal Cav-1 are feeding their cancer cells via recycled nutrients. That explains why a loss of stromal Cav-1 is such a good biomarker for identifying high-risk patients.

“The idea that a cancer cell’s local environment is important for tumor growth is now well-accepted by the cancer research community,” Dr. Lisanti says. “Now we show why this notion is correct.”

These studies were funded in part by grants from the NIH/National Cancer Institute, Susan G. Komen for the Cure, The American Cancer Society, The Breast Cancer Alliance, The Falk Medical Research Trust, The Landenberger Research Foundation and The Pennsylvania Department of Health.

Provided by Thomas Jefferson University (news : web)

Dickens DS, Cripe TP.

Division of Pediatric Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Ohio 45229, USA.

PURPOSE:

Sarcomas express cyclooxygenase (COX)-2, an inducible enzyme with known tumor-promoting activity.

COX-2 inhibition is efficacious against many cancer types but has not been tested for human sarcomas.

Matrix metalloproteinase (MMP) inhibitors also possess antiproliferative activity.

Because MMP inhibitor therapy induces COX-2 expression, the authors hypothesized that the combination of COX-2 and MMP inhibitors results in a synergistic antitumor effect.

METHODS:

Human osteosarcoma or rhabdomyosarcoma cells were injected into athymic mice.

Tumor development and growth were measured following treatment with a COX-2 inhibitor (celecoxib), an MMP inhibitor (doxycycline), or both.

The tumors were analyzed for necrosis, apoptosis, cyclooxygenase activity (PGE2 production), and MMP-2 levels.

RESULTS:

When treatment was started prior to tumor cell implantation, doxycycline inhibited osteosarcoma tumor growth alone and in combination with celecoxib (30% and 33% reduction, respectively).

An effect on osteosarcoma tumor implantation rates was noted in mice receiving doxycycline alone and in combination with celecoxib (12.5% and 6.25% reduction, respectively).

Established osteosarcoma and rhabdomyosarcoma tumors were inhibited only by combination therapy (36% and 55%, respectively).

A higher proportion of osteosarcoma tumors in the combination therapy group had more than 50% necrosis (3/7) when compared with control tumors (0/8).

Antitumor effects did not correlate with PGE2 levels, suggesting the observed interaction with doxycycline was due to previously described non-enzymatic effects of celecoxib.

CONCLUSIONS:

The authors’ preclinical data suggest that the combination of inexpensive, nontoxic, oral COX-2 and MMP inhibitors may be useful for the treatment of some types of solid tumors.

Kurmasheva RT, Dudkin L, Billups C, Debelenko LV, Morton CL, Houghton PJ.

Departments of Molecular Pharmacology, Biostatistics, and Pathology, St. Jude Children’s Research Hospital, Memphis, TN38105, USA.

PMID: 19789339 [PubMed - indexed for MEDLINE]

Artemisinin Blocks Prostate Cancer Growth and Cell Cycle Progression by Disrupting Sp1 Interactions with the Cyclin-dependent Kinase-4 (CDK4) Promoter and Inhibiting CDK4 Gene Expression^*

However, it remains unclear how Hedgehog pathway is involved in the pathogenesis of osteosarcoma. To explore the involvement of aberrant Hedgehog pathway in the pathogenesis of osteosarcoma, we investigated the expression and activation of Hedgehog pathway in osteosarcoma and examined the effect of SMOOTHENED (SMO) inhibition.

Results: To evaluate the expression of genes of Hedgehog pathway, we performed real-time PCR and immunohistochemistry using osteosarcoma cell lines and osteosarcoma biopsy specimens.

To evaluate the effect of SMO inhibition, we did cell viability, colony formation, cell cycle in vitro and xenograft model in vivo. PCR revealed that osteosarcoma cells over-expressed Hedgehog, PTCH, SMO, and GLI.

Real-time PCR revealed over-expression of SMO, PTCH, and GLI2 in osteosarcoma biopsy specimens’. These findings showed that Hedgehog pathway is activated in osteosarcomas.

Inhibition of SMO by cyclopamine, a specific inhibitor of SMO, slowed the growth of osteosarcoma in vitro. Cell cycle analysis revealed that cyclopamine promoted G1 arrest.

Cyclopamine reduced the expression of accelerators of the cell cycle including cyclin D1, cyclin E1, SKP2, and pRb. On the other hand, p21cip1 protein was up-regulated by cyclopamine treatment.

In addition, knockdown of SMO by SMO shRNA prevents osteosarcoma growth in vitro and in vivo.

Conclusions: These findings suggest that inactivation of SMO may be a useful approach to the treatment of patients with osteosarcoma.

Author: Masataka HirotsuTakao SetoguchiHiromi SasakiYukihiro MatsunoshitaHui GaoHiroko NagaoOsamu KunigouSetsuro Komiya
Credits/Source: Molecular Cancer 2010, 9:5

(PhysOrg.com) — Scientists at the University of Toronto and The Hospital for Sick Children (SickKids) have discovered a powerful new tool that can help predict the prognosis for patients with bone cancer and help doctors more accurately determine how aggressively they need to treat specific patients.

They found that the presence of a specific type of genetic mutation found in the tumours results in poorer outcomes for patients with osteosarcoma – the most common bone cancer in children and adolescents. The study is published in the current issue of Cancer Research.

The research team analyzed tumour DNA from osteosarcoma patients and found a novel region called osteo3q13.31, which contains three genes that were previously not known to be involved in the disease.

They used the presence or absence of a mutation in these genes – known as an osteo3q13.31 deletion – as an indicator to predict the disease outcome in osteosarcoma.

They studied 49 patients and found that a deletion resulted in poorer outcomes.

“This marker is an incredibly powerful tool. If the deletion is present, this suggests that the patient would need more aggressive therapy than if it is absent,” says principal investigator Dr. David Malkin, Paediatric Oncologist and Senior Scientist at SickKids, and Professor in the Department of Paediatrics at the University of Toronto.

“Hopefully, we would be able to avoid over treating patients who don’t need the most aggressive therapy, while ensuring that we aren’t under treating those who do.”

The advent of high-resolution technologies allowed the scientists to look at regions of DNA with much more clarity.

The scientists used a high-resolution tool called single-nucleotide polymorphism (SNP) array to look at copy number alteration (CNA).

CNA is a genetic phenomenon that occurs when some regions of the DNA are duplicated or deleted. Normally genes are present in two copies, with one copy inherited from each parent. CNAs are often found in osteosarcoma.

Every year, there are about 300 new cases of osteosarcoma in Canada, most of which occur in adolescents and young adults. The survival rate of about 65 per cent has not changed in about two decades.

While the first step is to use the new marker as a prognostic tool, Malkin says it may eventually be used as a therapeutic target, ultimately leading to improved survival rates for osteosarcoma.

Down the road, the marker may also be able to help determine prognosis in tissue cancers including carcinomas and sarcomas, he explains.

The research was supported by the Canadian Institutes of Health Research and SickKids Foundation.

Provided by University of Toronto (news : web)

MONDAY, Aug. 2 (HealthDay News) — An experimental vaccine based on an encephalitis virus may be able to block tumor growth in some advanced cancers by stimulating an immune response — even when an immune system has been suppressed, according to a study published online Aug. 2 in the Journal of Clinical Investigation.

Michael A. Morse, M.D., of the Duke University Medical Center in Durham, N.C., and colleagues treated 28 patients with advanced cancer, or cancer that had been unresponsive to treatment, with a vaccine created by removing replication genes from the Venezuelan equine encephalitis virus (an alphavirus) and replacing them with genes for the production of carcinoembryonic antigen, found in cancer cells. Over three months, the patients received up to four vaccine injections plus booster shots.

The researchers found that the vaccine generated an immune response against the tumor cells in some patients. Two patients with no evidence of disease remained in remission, two patients maintained stable disease, and one patient with pancreatic cancer had a lesion on his liver disappear. The remaining patients did not respond to the therapy. Patients with the smallest amount of tumor appeared to benefit most from the therapy.

“These data suggest that virus-like replicon particle-based vectors can overcome the presence of neutralizing antibodies to break tolerance to self antigen, and may be clinically useful for immunotherapy in the setting of tumor-induced immunosuppression,” the authors write.

Several study authors disclosed employee relationships with Alphavax.

Full Text

Treating cancers of the pelvis, brain and in children with new technique designed to ‘paint’ the tumor

HOUSTON, Aug. 3 /PRNewswire/ — The radiation oncologist’s mantra is to deliver the maximum dose of radiation to the malignant tumor, while limiting damage to healthy surrounding tissue. In proton therapy, this balance is achieved by using proton particles, accelerated to nearly the speed of light, to mimic the shape of a tumor and effectively deposit their energy within the confines of it with sub-millimeter precision.

New tools are enabling physicians at the Proton Therapy Center at The University of Texas MD Anderson Cancer to harness supercharged proton particles and conform them more precisely to the rugged landscape and uneven contours of a tumor. Using a technology known as pencil beam scanning, also known as spot scanning, protons are given the mission: Hone in on cancer cells and destroy. As much an art form as a war tactic, pencil beam proton therapy has the ability to treat the most complex of tumors, like those of the prostate, brain, base of the skull and eye, while leaving healthy tissue and critical structures virtually untouched. The powerful coupling of strength and accuracy offers unmatched capacity to treat a patient’s tumor without compromising quality of life during and after treatment.

In nearly a decade since pencil beam’s birth in a Swiss physics institute, the world’s leading practitioners in radiation science at MD Anderson’s Proton Therapy Center have integrated the tested technology into the institution’s multidisciplinary approach to patient care and translational cancer research.

A New Frontier for Proton Therapy

Proton therapy derives its advantage over conventional forms of radiation from its ability to deliver radiation doses to a targeted tumor with remarkable precision that avoids the surrounding tissue, which results in fewer side effects and improves tumor control. Most proton patients are treated with a technique known as passive scattering, which uses apertures to shape the proton beam and deliver a uniform dose to the tumor. Since opening in the spring of 2006, MD Anderson’s Proton Therapy Center has treated nearly 1,700 patients with this passive scattering technique [See Sidebar: A Best in Class Facility].

Pencil beam proton therapy delivers a single, narrow proton beam (which may be less than a millimeter in diameter) that is magnetically swept across the tumor, depositing the radiation dose like a painter’s brush strokes, without the need to construct beam shaping devices. The technology continues to build on the patient benefits already offered with proton therapy – more targeted, higher tumor dose, shorter treatment times, reduced side effects and increased treatment options – to treat complicated tumors perilously close to critical structures, such as the eye, brain and esophagus.

“The difference between passive scattering and pencil beam is like painting something with a can of spray paint versus using an airbrush,” said Andrew Lee, M.D., M.P.H., associate professor in the Department of Radiation Oncology at MD Anderson, and the director of the Proton Therapy Center. “Pencil beam is more like a very fine airbrush. Instead of needing a brass template to define the shape, the proton beam is made ultra fine to conform to the contours and landscape of a tumor.  When all these small beams are combined, they can cover the entire tumor volume with a high degree of conformality.  If the tumor is shaped like an egg, then the proton dose will look like an egg.”

Rapid Fire with Exquisite Precision

The Proton Therapy Center, which began treating patients with pencil beam in May 2008, continues to be the first in North America and one of only three clinical centers in the world to treat patients with this technology.  Because pencil beam does not require any external shaping devices, the treatment is less time consuming on a daily basis than passively scattered beams, with most treatments only taking a few minutes.

Using rapidly fired pulses, the pencil beam hits each planned spot within the tumor with the prescribed amount of radiation, starting at the deepest layer and working in succession, layer by layer, until the whole tumor is covered. Lee estimates that a typical tumor has between 1,000 to 2,000 separate spots arranged in up to 24 layers in a single pencil beam treatment. “We are able to maximize the protons generated and deposit more cancer-fighting energy directly into the tumor,” Lee said.

MD Anderson has used pencil beam proton therapy to treat patients with cancers of the brain, prostate, liver and esophagus – and has extended its use to begin treating tumors in pediatric cancer patients. Anita Mahajan, associate professor in the Department of Radiation Oncology at MD Anderson, who treats many of the Proton Therapy Center’s pediatric patients notes that it is an especially attractive option for solid tumors in children, who are generally more sensitive to the short- and long-term adverse effects of radiation. “Without the apertures, pencil beam deflects fewer neutrons into healthy tissue, which have been shown to increase the risk of second malignancies in young, still growing patients.”

As the only center in the nation treating patients with pencil beam proton therapy, Lee said that MD Anderson can offer children with cancer an even more targeted option to fight cancer and limit damage during and after treatment.

“This type of technology, along with our extensive experience in treating more types of childhood cancer than most other proton centers worldwide, continues MD Anderson’s mission to provide pediatric patient care with the most advanced, research-based therapies as are available to our adult patients,” he added.

MD Anderson has treated over 300 patients with pencil beam to date – both adult and pediatric patients.

Eloquent Treatment Planning Masters Complex Tumors

Pencil beam is only as good as the complex and intricate treatment planning systems used to direct the beam’s motion, depth and strength.  As these systems evolve to the extent of pencil beam’s capabilities, the team at MD Anderson’s Proton Therapy Center will tackle cancer’s most difficult tumors based on their shape and location in the patient.

“The beauty of pencil beam is that we have the ability to target the tumor with exquisite accuracy and spare surrounding healthy tissue and structures,” Mahajan said. “It’s best utilized when we need to conform high doses of radiation to irregularly shaped tumors embedded near or wrapped around critical structures in the head and neck, such as the eye or brain.” The advantage lies in the beam’s capacity to approach the tumor from multiple directions, creating a “U” shape around these structures and avoiding them entirely during treatment. Side effects common after standard radiation therapy are reduced and healthy organs are preserved because the radiation is confined to the tumor.

The future introduction of intensity modulated proton therapy at MD Anderson will also be possible as pencil beam delivery is further developed. Intensity modulated proton therapy uses the same pencil beam configuration, but the energy or intensity of the proton beam can be adjusted at any time to penetrate the tumor at varying depths. “This is the holy grail of radiation therapy,” Lee said. “Starting with pencil beam, and then working to develop treatment plans marrying the two together, is necessary to achieve this degree of sophistication for our patients.”

Zeroing in on Advances for the Patient

A pioneer in radiation oncology, MD Anderson has paved the way for more effective radiation therapy around the world. The Proton Therapy Center will continue to make strides in the field by making the combination of precision and potency found in pencil beam technology accessible to increasing numbers of patients in a clinical setting. Each patient who receives pencil beam treatment will be part of a growing body of research protocols at MD Anderson, examining proton therapy’s benefits over conventional radiation therapy and refining the technology to care for future generations of cancer patients with the best therapies available.

SIDEBAR: A BEST IN CLASS FACILITY

The Proton Therapy Center at MD Anderson stands as an international center of excellence for proton therapy, research and education.  Within its 96,000 feet of space the Center houses three treatment rooms equipped with giant gantries – three stories tall, 35 feet in diameter, weighing 196 metric tons – each capable of maneuvering the proton beam to precisely target the patient’s tumor.  A fourth room utilizes a stationary beam for larger tumors in the body, including tumors of the pelvis. Pencil beam technology is currently installed in one of the gantry rooms and is used to treat adult and pediatric patients.

The Center offers patients:

• Access to the most advanced radiation therapy stateside and MD Anderson’s world-renowned research, faculty and multidisciplinary patient care.

• Treatment for the most comprehensive range of disease sites including pediatric cancers and cancers of the head and neck, eye, prostate, brainstem, esophagus, lymphoma, liver and lung, among others.

• Reduced side effects and minimal damage to healthy tissue, which contribute to quality of life during and after treatment and enable patients to live longer, more fulfilling lives.

About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For six of the past eight years, including 2010, MD Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually in U.S. News & World Report.

www.mdanderson.org/proton

SOURCE The University of Texas MD Anderson Cancer Center

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We describe HIF expression and phenotypic effects of hypoxia, hypoglycaemia and HIF in Ewing’s sarcoma and osteosarcoma. Methods: HIF-1 alpha and HIF-2 alpha immunohistochemistry was performed on a Ewing’s tumour tissue array.

Ewing’s sarcoma and osteosarcoma cell lines were assessed for HIF pathway induction by Western blot, luciferase assay and ELISA.

Effects of hypoxia, hypoglycaemia and isoform-specific HIF siRNA were assessed on proliferation, apoptosis and migration.

Results:

17/56 Ewing’s tumours were HIF-1 alpha-positive, 15 HIF-2 alpha-positive and 10 positive for HIF-1 alpha and HIF-2 alpha.

Expression of HIF-1 alpha and cleaved caspase 3 localised to necrotic areas. Hypoxia induced HIF-1 alpha and HIF-2 alpha in Ewing’s and osteosarcoma cell lines while hypoglycaemia specifically induced HIF-2 alpha in Ewing’s.

Downstream transcription was HIF-1 alpha-dependent in Ewing’s sarcoma, but regulated by both isoforms in osteosarcoma.

In both cell types hypoglycaemia reduced cellular proliferation by over 45%, hypoxia increased apoptosis and HIF siRNA modulated hypoxic proliferation and migration.

Conclusions:

Co-localisation of HIF-1 alpha and necrosis in Ewing’s sarcoma suggests a role for hypoxia and / or hypoglycaemia in in vivo induction of HIF.

In vitro data implicates hypoxia as the primary HIF stimulus in both Ewing’s and osteosarcoma, driving effects on proliferation and apoptosis.

These results provide a foundation from which to advance understanding of HIF function in the pathobiology of primary bone sarcomas.

Author: Helen KnowlesKarl-Ludwig SchaeferUta DirksenNicholas Athanasou

Credits/Source: BMC Cancer 2010, 10:372

Scientists have used a genetically reprogrammed herpes virus and an anti-vascular drug to shrink spreading distant sarcomas designed to model metastatic disease in mice – still an elusive goal when treating humans with cancer, according to a study in the July 8 Gene Therapy.

Less than 30 percent of patients with metastatic cancer survive beyond five years, despite the aggressive use of modern combination therapies, including chemotherapy. This creates a significant need for new sarcoma therapies to treat metastatic disease, said Timothy Cripe, M.D., Ph.D., a physician/researcher in the division of Hematology/Oncology at Cincinnati Children’s Hospital Medical Center and the study’s senior investigator.

The study results are even more significant because the oncolytic herpes virus, HSV-rRp450, was given to the mice systemically to attack tumors via the blood stream instead of being injected directly into tumors.

“Systemic bio-distribution has been a major stumbling block for using virus vectors in gene transfer and virotherapy to treat cancer, but we show that viruses can be used systemically by giving them intravenously to get an anti-tumor effect,” Dr. Cripe said.

Also important to results of the current study was using the virus in conjunction with a drug (bevacizumab) that blocks the growth of tumor feeding-blood vessels. In the current study, researchers focused on spreading Ewing sarcoma and Rhabdomyosarcoma – cancers that form in muscle, bone and connective tissue.

Anti-angiogenic agents like bevacizumab are usually given first in combination cancer therapies because they help enlarge intercellular openings to tumor cells and ease the delivery of drugs, such as chemotherapies. In this study, however, the researchers discovered that bevacizumab has to be given after the virus to maximize the anti-tumor effect of the combined therapy. In fact, giving bevacizumab first lowered the virus’s uptake in cancer cells.

The rRp450 oncolytic virus used in the study was derived from herpes simplex type 1. The virus was genetically modified by scientists by removing a gene that makes the virus unable to replicate efficiently in dormant cells. This causes the virus to selectively target and replicate in rapidly growing cancer cells while leaving normally dormant healthy tissue cells alone.

After removing the one gene from the virus, researchers replaced it with a gene that encodes an enzyme that activates a class of anti-tumor chemotherapies called oxazaphosphorines. The overall therapeutic approach is for the virus to infect and degrade the cancer cells and then activate chemotherapy agents as anti-angiogenic agents cut off vascular growth and blood supply to the tumors.

In the current study, however, researchers treated the mice only with rRp450 and the anti-angiogenic drug bevacizumab. This allowed them to test whether the virus could be given systemically, how anti-angiogenic drugs affected virus tumor uptake and the impact this had on tumor growth.

In mice receiving bevacizumab prior to the rRp450, overall tumor shrinkage averaged 40 percent. In mice receiving rRp450 before bevacizumab, tumor size was reduced by an average of 75 percent. The researchers also reported that mice treated with rRp450 before bevacizumab had longer survival rates.

Results of the current study could be used immediately to help design subsequent research into treatment protocols for oncolytic viruses, particularly clinical trials involving combination therapeutic strategies, Dr. Cripe said. Clinical trials are underway in the United States and Europe using oncolytic herpes viruses similar to the one used in the current study.

Other researchers involved in the current study include the first author, Francis Eshun, M.D., and Mark Currier, Rebecca Gillespie, Jillian Fitzpatrick and William Baird, all of the Division of Hematology/Oncology at Cincinnati Children’s and its Cancer and Blood Diseases Institute. Funding support for the study from the Cincinnati Children’s Division of Hematology/Oncology, teeoffagainstcancer.org, the Katie Linz Foundation, the Limb Preservation Foundation, the American Cancer Society and the National Institutes of Health.

Source:
Nick Miller
Cincinnati Children’s Hospital Medical Center

Main News Category: Cancer / Oncology

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