Scientists spot missing link between cancer, high fat diet

• A newly developed molecular probe has allowed researchers to see nitric oxide in tumor microenvironments.
• The developers of the probe saw that, in mice, there was a link between increased nitric oxide levels where tumors develop and a high fat diet.
• Such an association between high fat diets and cancer could lead to advancements in prevention, diagnosis, and treatment.

A new study investigates the connection between dietary fat and nitric oxide (NO), high levels of which have been linked to inflammation. Inflammation, in turn, has been linked to cancer.

To observe NO on a molecular level, researchers at the Chan Lab of the Beckman Institute for Advanced Science and Technology at the University of Illinois at Urbana-Champaign (UIUC) developed a molecular probe that can produce images deep inside body tissue. Called BL660-NO, the probe provided the authors of the new study a look inside tumor microenvironments.

The researchers visually confirmed higher levels of NO in mice fed a high fat diet compared to mice on a low fat diet.

The study’s lead co-author, senior research associate Dr. Anuj Yadav, says they are “trying to understand how subtle changes in the tumor microenvironment affect cancer progression at the molecular level.”

The study was published in ACS Central Science.

Probing with BL660-NO

A molecular probe is a group of atoms or molecules that is used to analyze the properties of other molecules by examining the interactions between the probe and the molecules of interest. BL660-NO is a NIR (near-infrared) bioluminescent probe.

While other activity-based sensing (ABS) molecular probes have been developed, BL660-NO is the first purpose-built for imaging NO.

Professor Jefferson Chan, associate professor of chemistry at UIUC and the study’s principal investigator, says:

“Our group specializes in making designer molecules, which allows us to look at molecular features that are invisible to the naked eye. We design these custom-made molecules to discover things that weren’t previously known.”

Dr. Douglas D. Thomas, associate professor in the Department of Medicinal Chemistry and Pharmacognosy at UIUC, who was not involved in the study, told Medical News Today:

“They have developed a potentially useful tool to measure in vivo levels of NO, which is not easy to do. This tool may accelerate the pace of research regarding NO-associated diseases, including cancers.“

“The bioluminescence imaging-based probe will be extremely useful for detection of NO in a tumor microenvironment, said Dr. Deepak Nagrath, associate professor of biomedical engineering at the University of Michigan, who was also not involved in the study.

“Specifically, based on the recent interest in understanding the synergistic role of diet and chemotherapy, this probe will shed light on the dynamics and heterogeneity which exist in the cancers,” he told MNT.

What BL660-NO saw

The researchers conducted a diet study using breast cancer-carrying BALB/c mice. The mice who ate a high fat diet in which 60% of calories came from fat became obese and developed large tumors. They fed the control group a diet with 10% fat. They imaged nitric oxide levels in both groups.

The researchers also saw an increase in nitric oxide in the mice fed a high fat diet.

“The implication of this is that the tumor microenvironment is a very complex system, and we really need to understand it to understand how cancer progression works,” says co-author of the study Michael Lee, a student researcher in the Chan Lab.

“A lot of factors can go into this from diet to exercise,” says Lee, “external factors that we don’t really take into account that we should when we consider cancer treatments.”

Dr. Thomas was not entirely convinced.

“These are potentially interesting results. However, this is a mouse study, and based on their findings I don’t think you can make a causal mechanistic link between a high fat diet, amounts of NO detected, and a worse outcome without further experiments,” he said.

A complex link: nitric oxide and cancer

While the study supports the idea that nitric oxide is required in a tumor microenvironment, high doses of it are also used in chemotherapy as a means of killing tumor cells. This goes to show that the link between nitric oxide and cancer is complex.

Dr. Nagrath said nitric oxide acted in “a bimodal manner” in cancer cells.

“A low concentration of NO supports tumor growth, proliferation, and metastasis, whereas a high concentration kills the cancer cells through DNA damage and nitrosative stresses. This dual role of NO could also depend on diet and tumor microenvironment,” he said.

Dr. Thomas said the relationship between nitric oxide and tumors appeared to be tumor-type specific.

“In some cases, the presence of NO (or the enzymes that make NO) correlates to better patient prognosis, but more often NO is associated with more aggressive cancers. There are even some experimental cancer therapeutics that are designed to deliver NO to a tumor,” he said.

Prof. Chan said that thanks to this technology, they were able to spot this missing molecular link.

“Now that we know that this is happening, how do we prevent it, and how do we improve the situation?” he said.

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