Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Advances in tumor angiogenesis - Dendritic cells co-opted to the dark side

30.08.2004


Immune cells transform into blood-vessel cells in ovarian cancer




Researchers at the University of Pennsylvania School of Medicine discovered that in ovarian cancer immune cells can change into blood-vessel cells, and eventually promote the life-sustaining vasculature of the tumor. These findings were initially observed in a mouse model of ovarian cancer that the investigators generated and then confirmed in human ovarian cancer. This work may lead to new approaches to fighting solid tumors.

George Coukos, MD, PhD, and his team, Jose Conejo-Garcia, MD, PhD, and Fabian Benencia, PhD, all investigators in the Abramson Cancer Center and the Center for Research in Women’s Health and Reproduction, report their findings in this week’s online publication and the September issue of Nature Medicine.


"These results clearly deal with ovarian cancer, but we think that the concept is applicable to solid tumors in general," says Coukos. Ovarian cancer is the leading killer among gynecologic cancers, causing about 25,000 new cases a year and about 15,000 deaths annually in the U.S. "One of the problems is that it’s diagnosed late and we don’t have effective treatments for it.

"Dendritic cells play a central role in the generation of antitumor immune response," says Coukos. "As a result, it was believed that these were mostly good players in inducing tumor rejection." But when dendritic cells are part of the tumor microenvironment, instead of stimulating an immune response, they deviate from the program and are co-opted into tumor angiogenesis. "When the dendritic cell precursors are put in the tumor context they form blood vessels that are functional," notes Conejo-Garcia. In a mouse model in which ovarian tumors expressed high amounts of the proteins beta-defensin and VEGF-A, dendritic cell precursors were attracted to the tumor, where they turned into an endothelial-like cell type. Endothelial cells are the cells forming the inner lining of blood vessels. They are critical for building tumor blood vessels and promoting tumor growth.

For tumors to survive there needs to be a balance between factors that promote tumor growth such as angiogenesis and factors that control tumor growth such as immune response. Researchers have always considered these as two separate systems. "The breakthrough that this work provides is that there is indeed a tremendous interaction between these processes," says Coukos.

VEGF-A is the key for the transformation of dendritic cells, according to this study. VEGF proteins are ligands produced in the tumor that induce survival and proliferation of endothelial cells. When VEGF-A is overexpressed in tumors, dendritic cells change into endothelial cells, but in the absence of high VEGF-A levels or when VEGF-A is inhibited, the tendency of dendritic cells to convert is reversed. "I think what is fascinating in terms of biology is the plasticity that this cell has depending on its microenvironment," says Benencia.

It is well established that VEGF-A is the master switch for tumor angiogenesis, with a dose-dependent effect: in this case, dendritic cells were converted into endothelial-like cells only in the presence of high VEGF-A levels. "The levels of VEGF-A generated in our animal model of ovarian cancer resemble those seen in human ovarian cancer," says Coukos. "We have recapitulated what happens in human tumors." Thus, VEGF promotes tumor growth not only through angiogenesis but also through suppression of antitumor immune response, because these dendritic cells lose their ability to induce tumor rejection, which in turn may explain why some tumors are tolerated immunologically.

"We are the first to show that dendritic cell precursors in tumors build blood vessels," says Coukos. "This has previously been seen in vitro, where others have shown that monocytes or dendritic cells can turn into something that looks like endothelial cells, but no one has been able to demonstrate that this could happen in vivo and show its contribution to pathology and physiology."

The work has also revealed that the bone marrow – via dendritic cell precursors, which are produced in the marrow – is involved in angiogenesis. This observation raises clinically important questions as to the effects of supporting the bone marrow with growth factors during chemotherapy. Dendritic cells have surface molecules called CCR6, which are receptors for beta defensins and other molecules with chemoattracting properties. The team discovered that beta-defensins produced by the tumor attract dendritic cells to the tumor and thus contribute to angiogenesis. The team injected an antibody to CCR6 with an attached toxin that inactivates ribosomes. The toxin is internalized only by cells expressing CCR6, ultimately resulting in cell death. Selective killing of CCR6-expressing cells led tumors to shrink. "This has opened a door to a new therapeutic approach, which was not envisioned before," says Coukos.

Karen Kreeger | EurekAlert!
Further information:
http://www.upenn.edu

More articles from Life Sciences:

nachricht The dark side of cichlid fish: from cannibal to caregiver
20.04.2018 | Veterinärmedizinische Universität Wien

nachricht Enduring cold temperatures alters fat cell epigenetics
19.04.2018 | University of Tokyo

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

Im Focus: Like a wedge in a hinge

Researchers lay groundwork to tailor drugs for new targets in cancer therapy

In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...

Im Focus: The Future of Ultrafast Solid-State Physics

In an article that appears in the journal “Review of Modern Physics”, researchers at the Laboratory for Attosecond Physics (LAP) assess the current state of the field of ultrafast physics and consider its implications for future technologies.

Physicists can now control light in both time and space with hitherto unimagined precision. This is particularly true for the ability to generate ultrashort...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Diamond-like carbon is formed differently to what was believed -- machine learning enables development of new model

19.04.2018 | Materials Sciences

Electromagnetic wizardry: Wireless power transfer enhanced by backward signal

19.04.2018 | Physics and Astronomy

Ultrafast electron oscillation and dephasing monitored by attosecond light source

19.04.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>