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  #1  
Old 08-06-2012, 02:17 PM
gdpawel gdpawel is offline
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Default Treatment-induced damage to tumor microenvironment promotes chemoresistance

Catharine Paddock PhD.

A new study from the US finds that in the process of targeting and killing off cancer cells, chemotherapy may also spur healthy cells in the neighbourhood to release a compound that stimulates cancer growth, eventually leading to treatment resistance. They hope their finding will lead to better therapies for cancer and buy precious time for patients with advanced cancer.

Senior author Peter S. Nelson, of the Human Biology Division at the Fred Hutchinson Cancer Research Center in Seattle, and colleagues, write about their findings in a paper published online on 6 August in Nature Medicine.

Nelson told the media: "Cancer cells inside the body live in a very complex environment or neighborhood. Where the tumor cell resides and who its neighbors are influence its response and resistance to therapy."

The reason chemotherapy eventually fails when treating advanced cancer, said Nelson, is because the dose you would need to give the patient to wipe out the cancer would also kill the patient.

In the lab, you can "cure" almost any cancer: you just give a huge dose of toxic chemotherapy to the cancer cells in the petri dish.

But you can't do that to patients, because the high dose would not only kill cancer cells but also healthy cells, said Nelson.

So treatment of common solid tumors has to be given as smaller doses paced out in cycles, to give healthy cells time to recover in the intervals.

But the drawback is that this approach may not kill all the cancer cells, and those that survive can become resistant to subsequent cycles of the chemotherapy.

In their study, Nelson and colleagues found one mechanism through which this can happen.

They studied a type of normal, non-cancerous cell, the fibroblast, that lives near cancer tumors.

In animals, fibroblasts help maintain connective tissue, which is found throughout the body and acts like a "scaffolding" that holds other types of cells and tissue. Fibroblasts are also important for healing wounds and producing collagen.

But under other, non-usual circumstances, they can behave in unexpected ways.

When their DNA is damaged, for instance by chemotherapy, fibroblasts can release a broad range of compounds that stimulate cell growth.

Nelson and colleagues examined cancer cells from prostate, breast and ovarian cancer patients who had been treated with chemotherapy, and found specifically, that when the DNA of fibroblasts near the tumor is damaged by chemotherapy, they start producing a protein called WNT16B in the microenvironment of the tumor.

And, they also found, when the protein reaches a high enough level, it causes cancer cells to grow, invade surrounding tissue, and resist chemotherapy.

"The expression of WNT16B in the prostate tumor microenvironment attenuated the effects of cytotoxic chemotherapy in vivo, promoting tumor cell survival and disease progression", they write.

Researchers already knew, that the WNT family of genes and proteins are important for growth of both normal and cancer cells, but this study now reveals they may also have a role in promoting treatment resistance.

The researchers saw some WNT proteins increased 30-fold, which was "completely unexpected", said Nelson.

Cancer treatments are becoming increasingly specific, using precise "sniper" approaches to target key molecules rather than general "scatter gun" approaches such as damaging DNA.

The researchers say their findings suggest the microenvironment of the tumor can also play a role in the success or failure of these more precise approaches.

For example, the same cancer cell may react quite differently to the same treatment, in different microenvironments.

They suggest their discovery could help make treatments more effective, for instance by finding a way to block the tumor microenvironment's response.

Professor Fran Balkwill, a Cancer Research UK expert on microenvironments, told the press the study ties in with other studies that show "cancer treatments don't just affect cancer cells, but can also target cells in and around tumors".

Sometimes the effect can be helpful, said Balkwill, giving the example of when chemotherapy triggers health immune cells to attack nearby tumors.

"But this work confirms that healthy cells surrounding the tumor can also help the tumor to become resistant to treatment. The next step is to find ways to target these resistance mechanisms to help make chemotherapy more effective," he added.

Catharine Paddock PhD. "Chemotherapy Can Inadvertently Encourage Cancer Growth." Medical News Today. MediLexicon, Intl., 6 Aug. 2012

"Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B"; Yu Sun, Judith Campisi, Celestia Higano, Tomasz M Beer, Peggy Porter, Ilsa Coleman, Lawrence True & Peter S. Nelson; NatureMedicine, Published online 05 August 2012;DOI:10.1038/nm.2890

[url]http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.2890.html
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  #2  
Old 08-09-2012, 12:04 AM
gdpawel gdpawel is offline
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Default

"In the lab, you can cure almost any cancer: you just give a huge dose of toxic chemotherapy to the cancer cells in the petri dish. But you can't do that to patients, because the high dose would not only kill cancer cells but also healthy cells." How many times have I seen this happen with labs using single-endpoint assays (and basic leukemic type assays).

By examining drug-induced cell death events in native-state three-dimensional (3D) microclusters, the functional profiling platform recognizes the interplay between cells, not only stromal, but vascular elements, cytokines, macrophages, lymphocytes, mesenchymal cells, fibroblasts, smooth muscle cells, pericytes and other microenviromental factors known to be crucial for clinical response prediction. The human tumor primary culture microspheroid contains all of these elements.

The (slippery) polypropylene material prevents the attachment of fibroblasts and epithelial cells and encourages the tumor cells to remain in the form of three-dimensional (3D) floating clusters. Our body is already 3D (not 2D) in form, making this novel step better replicate that of the human body. When allowed to grow in vitro, "fresh" living cancer cells develop into these tiny microspheroid clusters that form a complex biosystem in which each malignant cell reacts upon it fellow colonists in subtle but important ways.

The microclusters recapitulate the human tumor environment, while the "3D" advancement recreates the extracellular matrix (metalloproteinases). The functional profiling platform studies cancer response to drugs within this microenvironment, enabling it to provide a snapshot of cancer's behavior within the human body and provides a more accurate representation of how cancer cells are likely to respond to treatment in the clinic.

Researchers at the University of Washington School of Medicine in Seattle have found that when cells become cancerous, they also become 100 times more likely to genetically mutate than regular cells. The findings may explain why cells in a tumor have so many genetic mutations, but could also be bad news for cancer treatments that target a particular gene controlling cancer malignancy.

If cancer cells do indeed become "mutator" cells, traditional chemotherapy and other "targeted" drugs may never be very effective against advanced tumors. This means that cancer cells in a tumor will have mutations that protect them from therapeutics.

A chemotherapy drug may target a particular oncogene, which is a gene that affects the malignancy of a particular cell. But if cancer cells are mutator cells, a single tumor may have cells with many different types of oncogenes and drug-resistant genes.

A chemotherapy drug may kill off some of the cancerous cells, but millions of other cells in the tumor will live on. To be effective, a chemotherapy treatment may have to target more than one oncogene: so-called combination chemotherapy. The more mutations, the further along the tumor may be in its development to malignancy or metastasis.

To lay the foundation for personalized cancer treatment, the ultimate "driver" could be the "functional" profiling platform. Cells speak to each other and the messages they send are interpreted via intracellular pathways. You wouldn't know this using genotype analysis. Phenotype analysis provides the window. It can test various cell-death signaling pathways downstream.
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Old 08-18-2012, 05:47 PM
gdpawel gdpawel is offline
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Default New Mechanism of Cancer Chemotherapy Resistance

Noncancerous fibroblasts when exposed to chemotherapy sustain DNA damage that drives the production of an array of factors that stimulate solid tumor cancer growth

Developing resistance to chemotherapy is a nearly universal, ultimately lethal consequence for cancer patients with solid tumors – such as those of the breast, prostate, lung and colon – that have metastasized throughout the body. A team of scientists led by the Hutchinson Center has discovered a key factor that drives this drug resistance – information that ultimately may be used to improve the effectiveness of therapy and buy precious time for patients with advanced cancer.

"Cancer cells inside the body live in a very complex environment or neighborhood. Where the tumor cell resides and who its neighbors are influence its response and resistance to therapy," said senior author Dr. Peter Nelson, of the Hutchinson Center’s Human Biology Division. The findings were published in Nature Medicine.

Co-authors included first author Dr. Yu Sun, staff scientist in the Nelson Lab; Drs. Peggy Porter of Human Biology; Ilsa Coleman of the Nelson Lab; and Dr. Tia Higano of the Clinical Research Division and University of Washington. Porter, Dr. Nicole Urban of the Public Health Sciences Division, and Dr. Beverly Torok-Storb of Clinical Research provided tissue samples for the study.

Nelson and colleagues found that a type of normal, noncancerous cell that lives in cancer’s neighborhood – the fibroblast – when exposed to chemotherapy sustains DNA damage that drives the production of a broad spectrum of growth factors that stimulate cancer growth. Under normal circumstances, fibroblasts help maintain the structural integrity of connective tissue, and they play a critical role in wound healing and collagen production.

Specifically, the researchers found that DNA-damaging cancer treatment coaxes fibroblasts to crank out a protein called WNT16B within the tumor neighborhood, or microenvironment, and that high levels of this protein enable cancer cells to grow, invade surrounding tissue and resist chemotherapy.

The researchers observed up to 30-fold increases in WNT production – a finding that was "completely unexpected," Nelson said. The WNT family of genes and proteins plays an important role in normal development and also in the development of some cancers but, until now, was not known to play a significant role in treatment resistance.

This discovery suggests that finding a way to block this treatment response in the tumor microenvironment may improve the effectiveness of therapy.

"Cancer therapies are increasingly evolving to be very specific, targeting key molecular engines that drive the cancer rather than more generic vulnerabilities, such as damaging DNA. Our findings indicate that the tumor microenvironment also can influence the success or failure of these more precise therapies." In other words, the same cancer cell, when exposed to different "neighborhoods," may have very different responses to treatment.

The major clinical reason that chemotherapy ultimately fails in the face of advanced cancer, Nelson said, is because the doses necessary to thoroughly wipe out the cancer would also be lethal to the patient.

"In the laboratory we can 'cure' most any cancer simply by giving very high doses of toxic therapies to cancer cells in a petri dish. However, in people, these high doses would not only kill the cancer cells but also normal cells and the host," he said.

Therefore, treatments for common solid tumors are given in smaller doses and in cycles, or intervals, to allow the normal cells to recover. This approach may not eradicate all of the tumor cells, and those that survive can evolve to become resistant to subsequent rounds of anti-cancer therapy.

For the study the team of researchers – which also involved investigators at the University of Washington, Oregon Health and Science University, the Buck Institute for Research on Aging, the Lawrence Berkeley National Laboratory – examined cancer cells from prostate, breast and ovarian cancer patients who had been treated with chemotherapy.

"This study is an example of collaborative, translational research that capitalizes on years of federally funded investments into the development of tissue banks and clinical trials in which we were able to track long-term patient outcomes. Investing in this type of infrastructure is critical but may take many years to see payoff," said Nelson, who serves as principal investigator of the Pacific Northwest Prostate Cancer SPORE, a federally funded, multi-institution research consortium led by the Hutchinson Center.

The National Institutes of Health, the National Cancer Institute, the Department of Defense and the Prostate Cancer Foundation funded the research.

Source: Fred Hutchinson Cancer Research Center
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  #4  
Old 08-18-2012, 05:48 PM
gdpawel gdpawel is offline
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Default The microenvironment contributes critically to drug response

What about the fibroblast matrix, the lymphatic vessels, the infiltrating monocytes, the T-cells, the B-cells and neutrophils: the vast complexities of the human tumor microenvironment? Real-life cancers grow as a complex organism that includes both malignant and non-malignant components.

It may include fibrous tissue, mesothelial cells, fibroblasts, endothelial cells, etc. In order to exhibit its most characteristic behavior patterns, a cancer cell needs to be surrounded by a colony of other cells, both normal and malignant.

By examining drug-induced cell death events in native-state 3D (three dimensional) microclusters, the functional profiling platform has the unique capacity to capture stromal, cytokines (chemokines), macrophages, lymphocytes, vascular and inflammatory cell interactions with tumor cells, known to be crucial for clinical response prediction.

The microclusters recapitulate the human tumor environment, while the "3D" advancement recreates the extracellular matrix (metalloproteinases). The platform studies cancer response to drugs within this microenvironment, enabling it to provide clinically relevant predictions to cancer patients. It is this capacity to study human tumor microenvironments that distinguishes it from other platforms in the field.

Tumors are very complex organisms. Ignoring this complexity, most studies of human cancer in culture have focused upon individual tumor cells that have been removed from their complex microenvironment.

Some previous methods of assays limited their analysis only to isolated tumor cells and failed to incorporate the crucial contribution of non-tumorous elements to the cancer phenomenon. Each of these microspheres contains all the complex elements of tumor biosystems that are found in the human body and which can impact clinical response.
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Last edited by gdpawel : 09-03-2012 at 05:32 PM. Reason: spelling errors
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