Melanoma stem cells' evasive talents

Jan 12, 2010

Melanoma, if not detected in its early stages, transforms into a highly deadly, treatment-resistant cancer. Although the immune system initially responds to melanoma and mounts anti-tumor attacks, these assaults are generally ineffective, allowing more advanced melanomas to win the battle and spread beyond the primary site. Now, researchers at Children's Hospital Boston and Brigham and Women's Hospital (BWH) shed light on how melanomas stimulate, yet ultimately evade, a patient's immune system. Their work, published online January 12 by the journal Cancer Research, also suggests ways drugs might block these tactics.

In 2008, the same team, led by Markus Frank, MD, of the Transplantation Research Center of Children's and BWH, and George Murphy, MD, chief of Dermatopathology at BWH, showed in the journal Nature that a key reason for virulence is a small group of tumor stem cells that are able to grow despite , allowing the tumor to re-grow and progress. They also showed that targeting these cells (identifiable by a molecule on their surface known as ABCB5) could successfully inhibit tumor growth in mice. (The ABCB5 technology has been licensed and is currently in clinical drug development.)

In their new paper, first author Tobias Schatton, PhD, of the Transplantation Research Center, and colleagues show that these ABCB5-positive cells also produce molecules that inhibit the body's natural immune attack, known as PD-1 and B7.2. These molecules work, they found, by triggering known as (T-regs), to dampen the normal anti-melanoma response. The T-regs are thus tricked into protecting the deadly melanoma stem cells from the body's own defenses.

"To my knowledge, this study provides the first evidence that cancer stem cells escape and down-regulate host antitumor immunity," says Frank, the study's senior investigator, also affiliated with the Department of Dermatology at BWH. "This might have important implications for cancer therapy, especially in malignant melanoma."

Additional experiments showed that melanoma stem cells stimulate surrounding cells' production of IL-10, a signaling molecule that suppresses the , and inhibit production of IL-2, which stimulates immune attack. The melanoma stem cells also produce fewer of the antigens that trigger immune responses, further evading immune attack.

The study adds to a growing body of evidence that melanoma stem cells have developed a repertoire of complementary strategies to outsmart host defenses, camouflaging them from the very immune cells and therapeutic agents that seek to destroy them. It also suggests new strategies for attacking the deadly skin cancer.

"Melanoma stem cell targeting holds promise for an absolute cure, because you're hitting the cells that really matter - the cells that drive tumor progression," says Murphy. "By understanding the precise molecular pathways whereby melanoma stem cells cajole the immune system into a permissive role, scientists are now closer to identifying ways of blocking or inhibiting such tactics."

For example, inhibition of PD-1 and B7.2 on melanoma stem cells could render them vulnerable not only to immune defenses, but also to treatments that are currently only effective against the more susceptible non-stem cell component of the tumor. Stripping away the stem cells' "protective shield" may allow a tumor to be killed without the possibility of it re-growing.

Melanomas are highly immunogenic cancers, initially provoking anti-tumor attacks, as evidenced by patients whose brown-black skin tumors seem to have partly dissolved away, producing regions of pink to white coloration where pigment previously existed. But ultimately, melanomas evade the immune system; until now, how the key cells that drive the melanomas' growth accomplish this has been a mystery.

The current work is relevant primarily to metastatic melanoma, which is often incurable, says Murphy. In their early, flat stages, melanomas can be cured surgically, but are potentially deadly once they grow as a skin elevation (sometimes no larger than a small pea) and spread to lymph nodes or vital organs. Scientists have long sought to find ways to target and destroy melanoma deposits that have already spread.

The research team is now planning to examine the ability of currently approved or investigational immunotherapeutic strategies to target and inhibit the immune-evasion tactics and immunological tolerance induced by melanoma stem cells. Specifically, they hope to participate in several ongoing or future clinical trials that target specific immunologic signaling pathways in melanoma patients (using anti-PD-1 antibodies, for example), to track the response of ABCB5-positive melanoma .

Explore further: Tailor-made cancer treatments? New cell culture technique paves the way

add to favorites email to friend print save as pdf

Related Stories

Inducing melanoma for cancer vaccine development

Mar 27, 2006

Cancer vaccines are being investigated in early-phase clinical trials around the world, with many of those trials recruiting patients with melanoma. Although tumor regressions have been seen in 10% to 20% of patients with ...

Study: Tumors inhibit immune system

May 29, 2006

Seattle scientists have shown that tumors can manipulate the immune system to stop it from attacking cancer cells, said a study published in Nature Immunology.

Recommended for you

Specific oxidation regulates cellular functions

5 minutes ago

For a long time, hydrogen peroxide has been considered as a dangerous metabolite that can damage cells through oxidation. This, however, is not its only role in the cell. Scientists from the German Cancer Research Center ...

New disease mechanism discovered in lymphoma

29 minutes ago

Programmed cell death is a mechanism that causes defective and potentially harmful cells to destroy themselves. It serves a number of purposes in the body, including the prevention of malignant tumor growth. ...

Researcher to cancer: 'Resistance will be futile'

8 hours ago

Turning the tables, Katherine Borden at the University of Montreal's Institute for Research in Immunology and Cancer (IRIC) has evoked Star Trek's Borg in her fight against the disease. "Cancer cells rapidly ...

How does prostate cancer form?

10 hours ago

Prostate cancer affects more than 23,000 men this year in the USA however the individual genes that initiate prostate cancer formation are poorly understood. Finding an enzyme that regulates this process ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.