A Tumor, the Embryo's Evil Twin

New York Times, MARCH 17, 2014
By Gerorge Johnson

An image of a section of a basal cell carcinoma. A gene involved with establishing symmetry in embryo organs can later run amok and help bring on this skin cancer.CreditSteve Gschmeissner/Science Photo Library

During her first encounter with cancer, Susan Sontag described a tumor as a “demonicpregnancy.” “This lump is alive,” she wrote in “Illness as Metaphor,” “a fetus with its own will.” She could hardly know that the comparison would become more than a figure of speech.

Since the book was published in 1978, scientists have been finding that the same genes that guide fetal cells as they multiply, migrate and create a newborn child are also among the primary drivers of cancer. Once the baby is born, the genes step back and take on other roles. But through decades of random mutations, old embryological memories can be awakened and distorted. What is born this time is a tumor.

There is no need, of course, for an alien impregnation. Cancer can be provoked by a carcinogen or a hormonal imbalance — or just a senseless, spontaneous mutation. Tipped from its equilibrium, a cell begins multiplying faster than it should. Two cells become four, then eight, then 16. Sontag’s demonic pregnancy, like “Rosemary’s Baby,” stirs to life.

Rough similarities between the growth of a tumor and the gestation of an embryo were first suggested more than a century ago. But no one could have guessed that the parallels would turn out to be so precise.

Consider the gene SHH. The name is short for sonic hedgehog. (Hedgehog genes were discovered in fruit flies and when mutated they cause the larvae to be covered with a profusion of bristles.) In a human embryo, sonic hedgehog is involved with establishing the bilateral symmetry of the brain, skeleton and other organs. Later in life it can run amok, interacting with genes like SMO (for smoothened — another fruit fly derivation) to bring on a human brain cancer called medulloblastoma and askin cancer called basal cell carcinoma.

Step by step, these and other genes play powerful roles in both creating and subverting a human life. In the early days of pregnancy, the primitive embryo — this rapidly dividing glob of cells — eats out a spot in the uterine lining using corrosive enzymes called proteases. Then it holds tight for the duration with the help of proteins like integrin, a kind of biological glue. Both types of molecules are also used by a cancer as it digs in and adheres to its berth.

Whether confronted by a tumor or a healthy pregnancy, the immune system reacts with alarm. To keep from being rejected like a mismatched organ transplant, the budding embryo sends chemical signals to quell the counterattack. Cancer cells engage in the same subterfuge.

As the embryo becomes established it secretes other enzymes, and these lead to the sprouting of blood vessels — a nourishing connection to the mother’s circulatory system. This process, called angiogenesis, is also exploited by a tumor as it fuels its growth by creating its own parasitic blood supply.

After hooking into the bloodstream, cancer seeds can spread to other parts of the body and sprout new malignancies. The process, called metastasis, appears to be driven by the same mechanism used in the embryo to dispatch freshly created cells to their proper locations.

In this complex metamorphosis, epithelial cells — the kind that stick together in sheets to form bodily tissues — are converted into loosely organized cells called mesenchyme. In this state they are free to move where they are needed to make body parts. Once they arrive they can regroup to form tissues and organs.

In a healthy embryo, this is an orderly affair. In cancer it leads not to new organs but to more tumors.

There is a point where cancer parts ways with its legacy from embryogenesis. Crucial to the development of a fetus is a phenomenon called apoptosis. The name, derived from ancient Greek, refers to the falling away of leaves from a tree or petals from a flower. Another name for it is cellular suicide.

In the burgeoning of cells that occurs during gestation, many are superfluous, and apoptosis encourages them to die. From a weblike flipper, distinguishable fingers emerge like sculpture from rock.

Once the new being is pushed into the world, apoptosis continues to be involved. Normal cells know to die when they become badly deranged. But an aspiring cancer soon learns how to wire around the self-destruct button. Spinning further out of control, it goes on to produce the mockery of a fetus called a tumor.

Confronted by the roiling chemical confusion inside a living cell, metaphors — the comparison of the strange to the familiar — can help scientists focus, separating signals from noise. But they can also beguile and mislead.

Sontag’s aim in her book was to explore how the language we invent for illness reflects society’s own diseases — its fairy-tale attitudes toward death, its addiction to unrestrained growth, consumption and violence.

Though she didn’t say so in the book, her own treatment for breast cancerinvolved a radical mastectomy and intense chemical warfare to stop the invader. In an optimistic moment she hoped that clinical advances would lead to a softening of the militaristic imagery as gentler therapies were developed, ones that stimulate the body’s own natural defenses.

Her enthusiasm was premature. Immune system therapy is recently showing renewed signs of promise. But when Sontag was given, later in life, a diagnosis of a cancer of the uterus and then — the one that killed her in 2004 — a cancer of the blood, the old warlike treatments remained the norm. For all the advances in understanding what cancer is like on a cellular level, that is still the reality today.

Website: talaya.net. Twitter: @byGeorgeJohnson.

A version of this article appears in print on March 18, 2014, on page D5 of the New York edition with the headline: A Tumor, the Embryo’s Evil Twin. Order Reprints|Today's Paper|Subscribe

Holding On and Hiding Out: How Cancer Cells Spread to the Brain and Thrive

From: On Cancer News and Insights from Memorial Sloan Kettering, By Eva Kiesler, PhD, Science Writer/Editor  |  Thursday, February 27, 2014

This image shows a breast cancer cell (green) clinging to a blood capillary (purple) in the brain.

Metastasis, the process that allows some cancer cells to break off from their tumor of origin and take root in a different tissue, is the most common reason people die from cancer. Yet most tumor cells die before they reach their next destination, especially if that destination is the brain. In people with lung cancer, for example, occasional tumor cells may enter the bloodstream and infiltrate the brain, but very few survive long enough to seed new tumors.

Now a team of Memorial Sloan Kettering scientists has looked into why most circulating tumor cells die upon reaching the brain and why, in exceptional cases, other cells don’t. Their latest study, published today in the journal Cell, identifies genes and proteins that control the survival of metastatic breast and lung cancer cells in the brain.

These survival factors might one day be targeted with drugs to further diminish people’s risk of metastasis. According to the study’s senior author, Sloan Kettering Institute Director Joan Massagué, a single mechanism is likely to enable cancer cells to colonize various organs, including the brain, in a number of disease types.

An Understudied Disease Type
Metastatic brain tumors occur in several types of cancer — including breast, lung, and colorectal cancer, among others — and are estimated to be about ten times more common than primary brain cancers. Until now, little research has been done into how metastatic brain tumors develop.

Dr. Massagué and his coworkers began to tackle this problem four years ago and have since learned that the brain is better protected than most organs against colonization by circulating tumor cells. To seed in the brain, a cancer cell must dislodge from its tumor of origin, enter the bloodstream, and cross a densely packed vasculature structure called the blood-brain barrier. Mouse experiments in which metastatic breast cancer cells were labeled and imaged over time revealed that a very small number were able to complete this journey, and of those cells that did make it to the brain, fewer than one in 1,000 survived.

“We didn’t know why so many of these cells die,” Dr. Massagué says. “What kills them? And how do occasional cells survive in this vulnerable state — sometimes hiding out in the brain for years — to eventually spawn new tumors? What keeps these rare cells alive and where do they hide?”

Dodging Death Signals
To answer these questions the researchers conducted experiments in mouse models of breast and lung cancer, two tumor types that often spread to the brain, investigating a panel of genes that have been linked to brain metastasis. Their research revealed that many cancer cells that enter the brain are killed by astrocytes — the most common type of brain cell — that secrete a protein called Fas ligand.

When cancer cells encounter this protein, they are triggered to self-destruct by the activation of an internal death program. The study also showed that the exceptional cancer cells that escape do so by producing a protein called Serpin, which acts as a sort of antidote to the death signals fired at them by nearby astrocytes.

Hugging Blood Vessels
The researchers used imaging methods to examine the behavior of these defiant metastatic cells in the brains of mice. They noticed that the surviving cells grew on top of blood capillaries — each cell sticking closely to its vessel “like a panda bear hugging a tree trunk,” Dr. Massagué says.

“This hugging is clearly essential,” he explains. “If a tumor cell detaches from its vessel, it gets killed by nearby astrocytes. By staying on, it gets nourished and protected, and may eventually start dividing to form a sheath around the vessel.”

Under the microscope, the researchers watched these sheaths grow into tiny balls, which eventually became tumors. “Once you’ve seen it, you can never forget this image,” Dr. Massagué says.

The scientists also did experiments to pinpoint the molecular basis of the cells’ behavior and showed that a protein produced by the tumor cells acts as a kind of Velcro, attaching the cells to the outer wall of a blood vessel.

Therapeutic Ideas
The findings give scientists new possibilities to understand and study the biology of metastasis, and could also lead to the development of new therapies that would work by strengthening the natural impediments to metastasis. The study identifies several mechanisms such drugs could target. Dr. Massagué is particularly interested in the ability of some tumor cells to hug blood vessels, as he suspects this behavior may be essential for the survival of metastatic cancer cells not only in the brain but also in other parts of the body where metastatic tumor growth can occur.

“Most cancer patients are actually at risk of having their tumor spread to multiple sites,” Dr. Massagué notes. For example, breast cancers can metastasize to the bones, lungs, and liver as well as to the brain. “What we may be looking at,” he adds, “is a future way to prevent metastasis to many organs simultaneously,” using drugs that make tumor cells let go of the blood vessels they cling to. 

This study was supported by the National Institutes of Health under grant numbers P01-CA129243 and U54-163167; a U.S. Department of Defence Innovator award, number W81XWH-12-0074; the Alan and Sandra Gerry Metastasis Research Initiative; and the Hope Funds for Cancer Research.

Breast cancer impersonates neurons to invade the brain

  • Article from New Science Magazine/Health
  • 20:00 06 January 2014 by Alyssa Botelho
  • For similar stories, visit the Cancer and The Human Brain Topic Guides
  • Able to pass for neurons(Image: NCI/SCIENCE PHOTO LIBRARY)

Able to pass for neurons <i>(Image: NCI/SCIENCE PHOTO LIBRARY)</i>

Women with breast cancer often enjoy several years in remission, only to then be given the devastating news that they have developed brain tumours. Now we are finally starting to understand how breast cancer cells are able to spread undetected in the brain: they masquerade as neurons and hijack their energy supply.

For every tumour that originates in the brain, 10 arrive there from other organ systems. Understanding how tumours spread, or metastasise, and survive in the brain is important because the survival rate of people with brain metastases is poor – only a fifth are still alive a year after being diagnosed.

Rahul Jandial, a neurosurgeon at the City of Hope Cancer Center in Duarte, California, wanted to explore how breast cancer cells are able to cross the blood-brain barrier and escape destruction by the immune system.

"If, by chance, a malignant breast cancer cell swimming in the bloodstream crossed into the brain, how would it survive in a completely new, foreign habitat?" Jandial says. He and his team wondered if breast cancer cells that could use the resources around them – neurotransmitters and other chemicals in the brain – would be the ones that survived and flourished.

To test the idea, they took samples of metastatic breast cancer cells from the brains of several women and grew them in the lab. They compared the expression of proteins involved in detecting and absorbing GABA – a common neurotransmitter that neurons convert into energy – in these cells with what happens in non-metastatic breast cancer cells.

Masters of disguise

Sure enough, the breast cancer cells taken from the brain expressed a receptor for GABA, plus a transporter protein that brings GABA into the cell, and a host of other compounds that convert GABA into energy. In this way, the metastatic tumour cells had in effect disguised themselves as neurons. No such machinery was seen in the non-metastatic breast cancer cells.

"The idea that metastasising cells can adopt a new identity, shielding them from intrinsic defence mechanisms, is very exciting and suggests that cancer cells are likely more plastic than previously suspected," says Ellen Carpenter, a neuroscientist at the University of California, Los Angeles, who was not involved in the work. "I think this is likely a tremendous advance in breast cancer research."

But understanding the neuronal disguise – a mechanism that other cancers may be using to spread in the brain, says Jandial – requires further work. For example, it's not clear whether breast cancer cells evolved the GABA machinery by chance over time, or somehow acquired it from their environment.

Still, Jandial hopes the results will lead to new chemotherapies based on existing drugs for brain cancers or neurodegenerative disease, or help us discover novel drugs to treat tumours that spread to the brain.

Journal reference: PNAS, DOI: 10.1073/pnas.1322098111