Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Engineered skin offers clues to melanoma development

13.06.2005


When it comes to the deadly skin cancer melanoma, studying functional tissue rather than cell lines may better provide insight into the disease’s development, according to new research from a Howard Hughes Medical Institute predoctoral fellow at Stanford University School of Medicine.



Though multiple genetic alterations are associated with melanoma development, scientists have not been able to establish a direct causal link between these alterations and human cancer growth. Determining whether these mutations have the potential themselves to induce cancer or simply play a supporting role also has been difficult.

To determine the impact of genetic alterations associated with human melanoma, Yakov Chudnovsky; his advisor, Paul Khavari; postdoctoral fellow Amy Adams, and colleagues generated human skin tissue containing cells selectively engineered to express specific mutations found in melanoma. They report their findings in the June 12, 2005, issue of the journal Nature Genetics, offering clues to the oncogenic potency of several genes implicated in the development of melanoma.


Melanoma is the deadliest form of skin cancer, resulting from the malignant transformation of cells called melanocytes. Over the past four decades, the incidence of melanoma has risen 15-fold, a more rapid increase than that of any other cancer. "The only current treatment is early detection and excision," Chudnovsky said. "But no treatment can substantially enhance patient survival once metastasis has occurred."

To simulate the environment in which melanoma naturally arises, the research team introduced one or more cancer-associated genes into human melanocytes, the pigment-producing cells that normally reside in the deepest layer of the skin. The genetically engineered melanocytes were then combined with keratinocytes, the cells that give skin its structure, to form a sample of human skin that was grafted onto laboratory mice. The mice were observed for up to six months and sacrificed at different time points to examine the skin grafts for signs of melanoma and to determine whether the cancer had metastasized.

The researchers began by introducing several mutant genes commonly found in human melanomas. These included genes that interfere with the retinoblastoma (Rb) and p53 tumor suppressor pathways, which normally act to keep cell growth in check, as well as human telomerase reverse transcriptase (hTERT), the enzyme that protects the ends of chromosomes during cell division. This enzyme is associated with the progression of many cancers. None of these mutant genes, when introduced individually or in combination, led to cancerous growth. But when a mutant form of Ras--produced by an oncogene that sends growth signals to a cell--was added to this combination, it produced clinical features of invasive human melanoma: darkly pigmented skin that progressed to ulcerated tumor nodules.

Melanoma was observed as early as one month after the oncogenic combination was introduced. The tumors demonstrated aggressive local invasion but did not metastasize.

Next, Chudnovsky and colleagues investigated whether interfering with either the Rb or p53 pathways could trigger melanoma. They found that in combination with Ras and hTERT, the expression of cyclin-dependent kinase 4 (CDK4),which promotes cell growth and inhibits Rb function, induced invasive melanoma in human tissue. Similarly, inhibition of p53, when combined with Ras and hTERT, resulted in invasive melanoma.

The scientists also investigated the role of elevated telomerase activity. In combination with other cancer genes, hTERT, the active protein in the enzyme telomerase, caused progressively invasive melanoma. In contrast, melanocytes that did not receive hTERT remained in an early stage of benign growth.

Finally, the team looked at the PI3K and Raf pathways, frequently implicated in the development of melanoma. They found the expression of active PI3K, together with CDK4, hTERT, and inhibition of p53, produced invasive melanoma growth indistinguishable from that caused by Ras. By contrast, B-Raf--the most common mutant gene in human melanoma--combined with CDK4, hTERT and inhibition of p53, could not cause full-scale melanoma.

When it comes to melanoma, PI3K and B-Raf often "show up at the scene of the crime," said Chudnovsky’s graduate advisor, Paul Khavari, but it has been unclear "which one is the murderer and which one is the accomplice." Based on this study, it appears that mutations that activate the PI3K cascade could be a primary pathway leading to melanoma.

"Our results highlight the importance of moving away from simplified cell transformation studies to studies of functional human tissue," Chudnovsky said. "Skin is easily accessible and can help us really understand how cancer develops, so we can develop new therapeutic targets."

Chudnovsky carried out this work in Khavari’s laboratory, in close collaboration with postdoctoral fellow and co-first author Adams. The team plans to use the human-tissue model of melanoma to evaluate potential treatments.

Jennifer Donovan | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden

nachricht The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Rainbow colors reveal cell history: Uncovering β-cell heterogeneity

22.09.2017 | Life Sciences

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>