Neurons support cancer growth throughout the body

CREDIT Venkatesh and Monje

Cancer cells rely on the healthy cells that surround them for sustenance. Tumors reroute blood vessels to nourish themselves, secrete chemicals that scramble immune responses, and, according to recent studies, even recruit and manipulate neurons for their own gain. This pattern holds true not just for brain cancers, but also for prostate cancer, skin cancer, pancreatic cancer, and stomach cancer. Stanford neuroscientists review how tumors exploit neuronal signals in Trends in Cancer.

There is no part of the body that isn’t well innervated,” says Michelle Monje of the Stanford University School of Medicine, who co-authored the article with PhD candidate Humsa Venkatesh. “The nervous system is an extremely arborized tree that reaches every aspect of every tissue and contributes importantly to tissue development. Those growth signals are already there, so why shouldn’t cancer cells co-opt them?

Cancer treatments often target tumors by cutting off blood vessels and other nutrient supply routes, so Monje and others are interested to learn whether it may be possible to target nerves via analogous therapies or by simply blocking secreted neural growth factors. The challenge is that growth-promoting signals vary by neuron and cancer type. Furthermore, blocking neural activity can be dangerous.

In the brain, modulating neuronal activity isn’t a great option because we don’t want to silence the brain. Brains need to be active and functioning,” says Monje. “But we can interrupt the specific molecular pathways that are being co-opted by the tumor.

Monje first became interested in neurons’ role supporting tumors while working on childhood glioma, a cancer that strikes in the precursors to glial cells in the developing brain. In 2015, her lab published a paper in Cell (DOI: 10.1016/j.cell.2015.04.012) that found that both adult and pediatric glioma cells grew faster when adjacent to highly active neurons.

The paper is part of a growing body of work indicating that cancer cells not only grow near nerves but also respond to the chemical signals that neurons secrete. Timothy Wang at Columbia recently published work in Cancer Cell (DOI: 10.1016/j.ccell.2016.11.005) that showed that recruitment of nerves into the tumor microenvironment is necessary and sufficient for stomach cancer progression, and that blocking a neurotransmitter in the nerves that line the stomach could represent a novel therapy. It’s only a first step, but it raises the possibility of treating cancers by targeting nearby nerves says Monje.

Seeds don’t tend to grow in the air. They have to be in the right soil,” she says. “Cancers are very much like that. They have to be in the right microenvironment.” Nerve cells and the chemicals they secrete can go a long way toward making cancer cells feel at home.

The connection between tumor cells and nerves opens many new questions but also sheds light on some longstanding cancer pathology observations. Brain cancer cells often cluster around neurons, a phenomenon called “perineuronal satellitosis,” and the extent of innervation in tumors has long been recognized as predictive of patient outcome. Migrating cancer cells also use nerves as shortcuts into new tissues.

However, so far researchers have only investigated neurons’ role in a handful of cancers, and the full molecular details of cancer-nerve partnerships are still being worked out.

Venkatesh and Monje. Neuronal Activity in Ontogeny and Oncology. Trends in Cancer 2017;3:89-112 [Article]


New ‘blood biopsies’ with experimental device may improve cancer diagnosis and follow-up

The investigators are conducting “liquid biopsies” by running blood through a postage-stamp-sized chip with nanowires 1,000 times thinner than a human hair and coated with antibodies, or proteins, that recognize circulating tumor cells. The device, the NanoVelcro Chip, works by “grabbing” circulating tumor cells, which break away from tumors and travel through the bloodstream, looking for places in the body to spread.

CREDIT Cedar-Sinai

Use of the chip in liquid biopsies could allow doctors to regularly and easily monitor cancer-related changes in patients, such as how well they’re responding to treatment. The research earned the lead investigators a place on the U.S. Cancer Moonshot program, an initiative led by former Vice President Joe Biden to make available more therapies to more patients and to prevent cancer.

It’s far better to draw a tube of blood once a month to monitor cancer than to make patients undergo repeated surgical procedures,” said Edwin Posadas, MD. “The power of this technology lies in its capacity to provide information that is equal to or even superior to traditional tumor sampling by invasive procedures.”

Although some forms of prostate cancer are so slow-growing that they pose little risk to patients, other forms of the disease are lethal. Identifying which patients have which type of disease has become a crucial area of study because prostate cancer is one of the leading causes of cancer death among men in the U.S. Nearly 27,000 U.S. men are expected to die from the disease in 2017, according to the American Cancer Society.
The research team has determined that in certain cancer cells, the nucleus is smaller than in other, more typical, cancer cells. Patients with the most advanced cases of aggressive prostate cancer have cells with these very small nuclei.

The investigators’ teamwork also revealed that very small nuclei are associated with metastasis, or cancer spread, to the liver and lung in patients with advanced cases of prostate cancer. Those nuclei developed before the metastases were detected. Identifying very small nuclei early in the disease progression may help pinpoint which patients have high risk of developing cancer that can spread and be fatal.

Hsian-Rong Tseng, PhD, professor, Department of Molecular and Medical Pharmacology in the David Geffen School of Medicine at UCLA and the other lead investigator, said that his work with Posadas is focused on improving the quality of life for cancer patients.

We’re on a mission to dramatically change patients’ everyday lives and their long-term outcomes,” Tseng said. “We now have powerful new tools to accomplish that.”

Posadas and Tseng join an elite cadre of academicians, technology leaders and pharmaceutical experts as partners in the Blood Profiling Atlas in Cancer (BloodPAC) Project, a Moonshot program. Participants will collect and share data gathered from circulating tumor cells. Posadas and Tseng expect to contribute microscopic images from 1,000 circulating tumor cells that have not yet been analyzed, as well as additional data and cells they have cataloged.

For the past five years, Posadas and Tseng have collected blood samples from cancer patients to profile and analyze the circulating tumor cells and other components. That process has helped them understand how prostate and other cancers evolve. The two investigators and their teams hope their findings will contribute to developing effective, targeted treatments for many types of cancer.

Minimally invasive methods to both diagnose and follow cancer, through simple blood tests, offer a unique and novel approach that can lead to earlier diagnosis and treatment, leading to more cures,” said Robert A. Figlin, MD, director of the Division of Hematology Oncology and deputy director of the Samuel Oschin Comprehensive Cancer Institute at Cedars- Sinai.