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Old 01-07-2015, 08:59 PM
gdpawel gdpawel is offline
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Default 3-D culture system for pancreatic cancer

Pancreatic cancer is one of the most deadly forms of cancer, with only 6 percent of patients surviving five years after diagnosis. Today, Cold Spring Harbor Laboratory (CSHL) and The Lustgarten Foundation jointly announce the development of a new model system to grow both normal and cancerous pancreatic cells in the laboratory. Their work offers the potential to change the way pancreatic cancer research is done, allowing scientists to interrogate the pathways driving this devastating disease while searching for new drug targets.

In work published recently in Cell, the research team describes a three-dimensional "organoid" culture system for pancreatic cancer. Co-led by David Tuveson, CSHL Professor and Director of Research for The Lustgarten Foundation, and Hans Clevers, Professor and Director of the Hubrecht Institute and President of the Royal Netherlands Academy of Arts and Sciences, the team developed a method to grow pancreatic tissue not only from laboratory mouse models, but also from human patient tissue, offering a path to personalized treatment approaches in the future.

All cancer research relies on a steady supply of cells - both normal and cancerous - that can be grown in the laboratory. By comparing normal cells to cancer cells, scientists can then identify the changes that lead to disease. However, both types of pancreatic cells have been extremely difficult to culture in the laboratory.

Furthermore, the normal ductal cells that are able to develop into pancreatic cancer represent about 10 percent of the cells in the pancreas, complicating efforts to pinpoint the changes that occur as the tumor develops. Until now, scientists have been entirely unable to culture human normal ductal pancreatic cells under standard laboratory conditions. Because of these limitations, most pancreatic cancer research relies on genetically engineered mouse models of the disease, which can take up to one year to generate. "With this development, we are now able to culture both mouse and human organoids, providing a very powerful tool in our fight against pancreatic cancer," explains Tuveson.

The organoids are entirely made up of ductal cells, eliminating the surrounding cell types that often contaminate samples from the pancreas. They grow as hollow spheres within a complex gel-like substance filled with growth-inducing factors and connecting fibers. Once they have grown to a sufficient size, the organoids can be transplanted back into mice, where they fully recapitulate pancreatic cancer. "We now have a model for each stage in the progression of the disease," says Chang-Il Hwang, Ph.D., one of the lead authors working in The Lustgarten Foundation's Pancreatic Cancer Research Lab at CSHL directed by Dr. Tuveson.

Traditionally, cancer cells are isolated during surgery or autopsies. Unfortunately, approximately 85 percent of cancer patients are ineligible for surgery at the time of diagnosis, either because the tumor is entwined in critical vasculature or the disease has progressed too far. Researchers therefore have had limited access to patient samples. The new research provides a way for scientists to grow organoids from biopsy material, which is comparatively easy to obtain. "Biopsies are the standard for diagnosis," says Dannielle Engle, Ph.D., also a lead author on the paper. "We can now rapidly generate organoids from any patient, which offers us the potential to study the disease in a much wider population."

The team is now working to create a repository of pancreatic tumor samples, coordinating with the National Cancer Institute. "We hope to make this available to the entire pancreatic cancer research community," says Tuveson. Additionally, Lindsey Baker, Ph.D., another lead author of the paper, has started holding an "organoid school" for other researchers, and has already taught six laboratories from around the world this technique.

References:

This work was supported by The Lustgarten Foundation for Pancreatic Cancer Research, the Cold Spring Harbor Laboratory Association, the National Cancer Institute Center for Cancer Genomics, the Carcinoid Foundation, PCUK, and the David Rubinstein Center for Pancreatic Cancer Research at MSKCC. In addition, the work was supported by Stand Up to Cancer/KWF, the STARR foundation, the United States Department of Defense, the Sol Goldman Pancreatic Cancer Research Center, the Italian Ministry of Health, Sociedad Española de Oncología Médica, Louis Morin Charitable Trust, the Swedish Research Council, The Kempe Foundations, the Swedish Society of Medicine, the Damon Runyon Cancer Research Foundation, the Human Frontiers Science Program, the Weizmann Institute of Science Women in Science Award, the American Cancer Society, and the Hearst Foundation.

"Organoid Models of Human and Mouse Ductal Pancreatic Cancer" appeared online in Cell on December 31, 2014, and will appear in the January 15, 2015 print edition. The authors are: Sylvia Boj, Chang-Il Hwang, Lindsey Baker, Iok In Christine Chio, Dannielle Engle, Vincenzo Corbo, Myrthe Jager, Mariano Ponz-Sarvise, Hervé Tiriac, Mona Spector, Ana Gracanin, Tobiloba Oni, Kenneth Yu, Ruben van Boxtel, Meritxell Huch, Keith Rivera, John Wilson, Michael Feigin, Daniel Öhlund, Abram Handly-Santana, Christine Ardito-Abraham, Michael Ludwig, Ela Elyada, Brinda Alagesan, Giulia Biffi, Georgi Yordanov, Bethany Delcuze, Brianna Creighton, Kevin Wright, Youngkyu Park, Folkert Morsink, I. Quintus Molenaar, Inne Borel Rinkes, Edwin Cuppen, Yuan Hao, Ying Jin, Isaac Nijman, Christine Iacobuzio-Donahue, Steven Leach, Darryl Pappin, Molly Hammell, David Klimstra, Olca Basturk, Ralph Hruban, George Johan Offerhaus, Robert Vries, Hans Clevers, David Tuveson. Abstract. DOI: 10.1016/j.cell.2014.12.021

[url]http://www.cell.com/cell/abstract/S0092-8674(14)01592-X

Citation: Cold Spring Harbor Laboratory. "3-D culture system for pancreatic cancer has potential to change therapeutic approaches." Medical News Today. MediLexicon, Intl., 6 Jan. 2015
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Old 01-07-2015, 09:01 PM
gdpawel gdpawel is offline
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Default Tumor Organoid Technology

They are trying to fill the gap between simple cancer cell-lines and xenografts.

The pathologist establishes a cell-line (immortalizes it) with your tumor cells. A cell-line is a product of immortal cells that are used for biological research. Cell lines can perpetuate division indefinitely. Regular cells can only divide approximately 50 times.

Cell lines are useful for experimentation in labs as they are always available to researchers as a product and do not require harvesting (acquiring of tissue from a host) every time cells are needed in the lab. They can clone cells from a cell line (HeLa cells).

Problem is, cell lines don't recapitulate drug response patterns which exist in the body.

Here is some information about the difference between "Cell Lines" vs "Fresh Cells."

[url]http://cancerfocus.org/forum/showthread.php?t=3702

Xenografts are transplantable tumors in mice. The process begins with the acquisition of fresh tumor tissue obtained from a biopsy (FNA, core, or surgical) which is then engrafted (implanted) in its entirety (including its surrounding stromal compartment) into a specialized mouse host.

By implanting the tumor, plus its surrounding microenvironment, the animal tumor grafts continue to closely resemble the patient's own tumor with high genetic correlation. Tumor engraftment and growth occurs over a 12-20 week time period.

The problem with tumor xenograph experiments is that they are usually done on SCID mice - aka, mice with ZERO immune system. They also use nude mice, which don't have a thymus, and therefore no T cells.

Clinicians have been transplanting tumors into mice and then treating the mice to predict response in humans for more than 30 years. The molecular signatures are really useless for the type of chemotherapy used in 95% of cases which are treated with chemotherapy and are useless with regard to drug combinations.

So, either of the above methods are no where even close to what the guys I know already do.

Now, this organoids method is supposed to be using three-dimensional structures grouped together and spatially arranged like an organ or tissue.

That is interesting, because cancer is already in 3D conformation. Cell-based functional profiling (what my guys do) cultures "fresh" live tumor cells in 3D conformation and profiles the function of cancer cells (is the whole cell being killed regardless of the targeted mechanism or pathway).

It distinguishes between susceptibility of cancer cells to different drugs in the same class and the susceptibility to combinations. In other words, which combinations are best and in what sequence would they be most effective.

However, they are isolating tumor cells from a patient and "growing" them in the laboratory. There is nothing being grown in modern functional tumor cell profiling with cell-death assays. Cells are taken fresh "live" in their three-dimensional, floating clusters, cultured in conical polypropylene microwells for 96 hours to increase the proportion of tumor cells, relative to normal cells. So, there is no manipulation of isolated cancer cells to make them grow.

Older technology looked to see which drugs inhibited the cancer cells' growth (cell-growth), not which chemotherapies actively killed the tumor cells (cell-death). Cancer wasn't growing faster than other cells, it was just dying slower. The newer technology connects drugs to patients by what "kills" their cells, not by what "slows" them down.

There is a problem with "growing" or "manipulating" tumor cells in any way. Cells "grown" in the lab will not behave the same way as the actual cancer cells do in your body's own environment. When looking for cell-death-related events, which mirror the effect of drugs on living tumors, cells are generally not "grown" or "amplified" in any way. The object is occurrence of programmed cell death in cells that come into contact with therapeutic agents.

"Cell-growth" assays are performed on pre-cultured and amplified monolayer cells (testing subcultured cell population), and studies by the NCI Navy medical oncology branch did not find that monolayer assays performed on pre-cultured, pre-amplified tumor cells clearly gave clinically relevant results.

Analysis of a relatively small number of "isolated" cancer cells cannot yield the same quality information as subjecting "living" cells to chemotherapeutic agents, begging the question of whether or not it can accurately predict which drugs will work and which will not.

The problem with the "cell-growth" method is that the "cloning" process can create changes in the cell biology so that the cancer cells may not react the same in the presence of chemotherapy agents as the actual cancer cells in your body will - kind of like creating an artificial environment. It takes a few weeks longer because of the timeframe to "grow" the cells.
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