Embryonic signal drives pancreatic cancer and offers a way to kill it

[Rich66]

Public release date: 3-Nov-2011
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Contact: Lisa Lyons
elyons@cell.com
617-386-2121
Cell Press
Embryonic signal drives pancreatic cancer and offers a way to kill it

Pancreatic cancer is a particularly challenging one to beat; it has a tendency to spread and harbors cancer stem cells that stubbornly resist conventional approaches to therapy. Now, researchers reporting in the November issue of Cell Stem Cell, a Cell Press publication, have evidence to suggest there is a way to kill off those cancer stem cells. The target is a self-renewal pathway known for its role not in cancer but in embryonic stem cells.
"I don't think the cancer stem cells have any direct link to embryonic development, rather they are using this developmental pathway for their uncontrolled self-renewal capacity," said Christopher Heeschen of the Spanish National Cancer Research Centre in Madrid. "This pathway is completely inactive in adult tissue. We've checked many tissues and there is zero – no detectable expression at all."
The so-called Nodal/Activin pathway's embryonic ties and absence from other tissues present a real opportunity. It suggests you could target the molecular pathway without harming other adult cells. Heeschen's team has now shown that approach to therapy does seem to work in mice.
They first demonstrated the important role of the Nodal/Activin pathway in cancer stem cells derived from human pancreatic cancer. When that signal was blocked, normally resistant pancreatic cancer stem cells became sensitive to chemotherapy.
The researchers then moved on to experiments in mice with established tumors seeded from human cancer cells. Treatment of those animals with the pathway inhibitor plus standard chemotherapy eliminated those stem cells.
"The dual combination therapy worked strikingly well," Heeschen said. "The mice responded with 100 percent survival after 100 days." That's compared to mice not receiving the therapy, which bore large tumors and died within 40 days of implantation.
That two-part treatment wasn't enough to tackle pancreatic cancer when intact tumor tissue was implanted into mice as opposed to just cancer cells, the researchers found. Heeschen says that's because those cells were nestled within a supportive "stroma." That protective tissue delivered the Activin signal and prevented the drug combination from reaching the cells.
To get around that, Heeschen and his colleagues added a third ingredient to therapy, an inhibitor intended to target the stroma. The three-pronged approach translated into long-term, progression-free survival for the mice.
Interestingly, Heeschen says the animals' tumors didn't show signs of shrinking even as they were defeated. "They were more or less dead tissue. They were senescent with no cancer stem cells – just sitting there," he said.
Those tissues apparently had no ability to form new tumors. The findings suggest that tumor regression isn't always the key thing to look for. It also shows that drugs designed to target cancer stem cells alone are promising, but only in combination with other drugs.
"The concept that you can hit cancer stem cells and tumors will melt away must be abandoned," Heeschen said. "You have to treat the entire cancer - the stroma, cancer stem cells and differentiated cells - as a complex. "
Heeschen says there are hints that this embryonic pathway might have important roles in other forms of cancer, including breast, lung and colorectal cancers. That's something they will now test in further studies.

[gdpawel]

Rich

This looks similar to research being done by an international team from Monash, Stanford and John Hopkins universities which represents not just the potential for new drugs but also a novel way of approaching cancer treatment.

The study, published in the "Nature Medicine" journal, showed that the regrowth of SCLC cells could be blocked by a drug that targets growth signals, which, in healthy cells, control organ development and repair.

Blocking the embryonic signalling pathway, known as Hedgehog (Hh), could form basis of new SCLC treatments. By using drugs to inhibit the Hedgehog signalling, they should be able to increase the effectiveness of chemotherapy and reduce the risk of cancer relapse.

Vismodegib (GDC-0449) is such a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), and has produced promising anti-tumor responses in clinical studies of cancers driven by mutations in this pathway.

Cancer stem cells (CSCs), are aggressive cells thought to be resistant to current anti-cancer therapies and which promote metastasis, are stimulated via a pathway that mirrors normal stem cell development. Disrupting the pathway, researchers are able to halt expansion of CSCs.

One approach is to force the CSCs into a differentiated state, thereby impairing stem characteristics, such as self-renewal. Interference with the Notch, Wnt, or Hedgehog pathways that are thought to regulate differentiation, are strategies that have been proposed.

Cell-based functional profiling labs have recognized the interplay between cells, stroma, vascular elements, cytokines, macrophages, lymphocytes and other environmental factors. This lead to their focus on the human tumor primary culture microspheroid (microclusters), which contains all of these elements.

In their earlier work, they endeavored to isolate tumor cells from their benign constituents so as to study "pure" tumor cells. As time went on, however, they found that these disaggregated cells were artificially sensitized to the effects of chemotherapy and provided false positive results in vitro.

Early work by Beverly Teicher and Robert Kerbel that examined cells alone and in three-dimensional (3D) structures, lead to the realization that cancer cells inhabit a microenvironment. Functional profiling labs now study cancer response to drugs within this microenvironment, enabling them to provide clinically relevant predictions to cancer patients.

It is their capacity to study human tumor microenvironments that distinguishes them from other lab platforms in the field. And, it is this capacity that enables them to conduct discovery work on the most sophisticated classes of compounds that influence cell signaling at the level of notch, hedgehog and WNT, among others (Gonsalves, F, et al. (2011).

An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of WNT/wingless signaling pathway (PNAS vol. 108, no. 15, pp. 5954-5963). With this clinically validated platform they are now positioned to streamline drug development and advance experimental therapeutics.

Source: Dr. Robert Nagourney; Rational Therapeutics, Inc.

[Firework]

Interesting Article. Thanks for sharing. I am new to this site but have seen a few other articles out of Nature Magazine. Have they got a web page?

[gdpawel]

http://www.nature.com/

[gdpawel]

The Hedgehog signaling pathway is a target of growing interest in the oncology community. It represents a new way of understanding and potentially attacking the progression and reoccurrence of cancer. The Hedgehog pathway is normally active during embryonic development and regulates tissue and organ formation.

When abnormally activated in adults the Hedgehog pathway is believed to play a central role in allowing the proliferation and survival of cancer cells, including pancreatic cancer, prostate cancer, small cell lung cancer, breast cancer, hematologic cancers, skin cancers, and certain brain cancers.

In addition, recent evidence points to a potentially important role for the Hedgehog pathway in tumor progenitor cells. Tumor progenitor cells are resistant to standard anti-cancer agents and radiation, and are therefore suspected to be responsible for disease relapse following treatment with conventional therapeutic agents.