Cigarette smoke reprograms the cells that surround head and neck squamous cell carcinoma (HNSCC) cells and drives the cancer’s aggressiveness, according to researchers at Thomas Jefferson University.
“Cigarette smoke changes the metabolism of cells in head and neck squamous cell carcinomas, making the tumors more efficient as an ecosystem to promote cancer growth,” said Ubaldo Martinez-Outschoorn, MD, associate professor in the Department of Medical Oncology and researcher at the Sidney Kimmel Cancer Center-Jefferson Health, who led the study.
Tumors comprise cancer cells that grow out of control and non-cancerous cells that support the tumor. More than half of the cells in tumors are support cells, and they create what scientists call the tumor stroma. The most common cell type in the tumor stroma are fibroblasts, which help maintain tissue architecture.
In previous research, Martinez-Outschoorn and his colleagues found that interactions between fibroblasts and cancer cells promote tumor growth.
“We found previously that tumors in human and animal models of head and neck squamous cell carcinoma thrive when these distinct groups of cells support each other,” said Martinez-Outschoorn.
Cancer cells make use of metabolic products generated by the surrounding fibroblasts in order to obtain energy and fuel their growth.
“That’s where tumors are most aggressive,” Martinez-Outschoorn said.
“Knowing that cigarette smoke is the strongest risk factor for this cancer type, we wanted to better understand how it changes the metabolism of the different cells in the tumor,” said graduate student and researcher Marina Domingo-Vidal.
In the current study, the researchers exposed fibroblasts to cigarette smoke. The fibroblasts increased a particular type of metabolism called glycolysis, which produces metabolites used by the nearby cancer cells to help fuel their growth. These cancer cells also acquired malignant features such as increased mobility and resistance to cell death. The enhanced support of the tobacco-exposed fibroblasts caused larger tumors in a mouse model of the disease.
The researchers also found a protein on tobacco-exposed fibroblasts that appeared to drive these metabolic changes.
“The protein, called monocarboxylate transporter 4, is a major mechanism by which cigarette smoke exerts cancer aggressiveness, and we’ve shown how to manipulate and hopefully reverse it,” said Domingo-Vidal.
“We’ve also seen that smoke-exposed fibroblasts interact with other cells in the tumor stroma, such as the cells of the immune system,” said Domingo-Vidal. “A healthy immune system is responsible for recognizing and attacking malignant cells, so it will now be interesting to understand how these altered fibroblasts might influence the efficacy of current immunotherapies.”
The study has set the foundation for a clinical trial where the researchers hope to shut down the negative metabolic state induced by cigarette smoke, they said.
“Our finding is part of a growing interest in understanding the metabolic relationship between different cells in the tumor environment and how we can target them to improve patient outcomes,” said Joseph Curry, MD, associate professor in the Department of Otolaryngology-Head and Neck Surgery.
The clinical trial will use a two-pronged approach to combat the cancer. It will combine a drug approved by the Food and Drug Administration (FDA) for diabetes called metformin that will target the cancer cells’ altered metabolism with an FDA-approved immunotherapy called durvalumab, a checkpoint or PD-L1 inhibitor that takes the brakes off of the immune system.
“We think metformin and durvalumab might have a synergistic effect on the cancer, where metformin slows the bad players, the cancer cells, and durvalumab grows the strength of the good players, the immune cells,” said Curry.
The study, “Cigarette Smoke Induces Metabolic Reprogramming of the Tumor Stroma in Head and Neck Squamous Cell Carcinoma,” was published by Molecular Cancer Research.
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