A group of Thomas Jefferson University researchers has recently found that cigarette smoke can make head and neck cancers grow more aggressively. Cancer in these regions is the sixth most common form of malignancy in the world, with most of these cases arising from head and neck squamous cell carcinomas (HNSCC). This carcinoma manifests in the outer layer of the skin and mucous membranes of the nose, mouth, and throat. In their most recent work, published in the journal Molecular Cancer Research, these researchers found that cigarette smoke promotes metabolic changes in cancer cells that promote cancer development.
“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,” explained study leader Ubaldo Martinez-Outschoorn, MD, associate professor in the Department of Medical Oncology. Martinez-Outschoorn is also a researcher at the Sidney Kimmel Cancer Center at Jefferson.
The tumor microenvironment consists of many cells other than those expressing malignancy. These non-malignant cells compose the tumor stroma, which provides an extracellular matrix that supports cancer growth. The fibroblast, which produces collagen and composes most of the tumor stroma, is integral to maintaining tissue structure.
Alongside Joseph Curry, MD, Martinez-Outschoorn previously found that these fibroblasts interact with cancer cells to ultimately perpetuate tumor development. Curry is an associate professor in the Department of Otolaryngology-Head and Neck Surgery at Jefferson.
“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. He explained that cancer cells utilize the metabolic products created by stromal cells such as fibroblasts to sustain energy for proliferation.
Background of the Jefferson Study
In their work, the research team first exposed fibroblast cells to cigarette smoke. They observed metabolic changes in these fibroblast cells, specifically an increase in glycolysis. Glycolysis is the metabolic process by which cells produce energy in the absence of oxygen and is responsible for creating lactic acid in the muscles during intense exercise.
By increasing rates of glycolysis, these fibroblasts in the stroma produce metabolites that cancer cells use for growth. These cancer cells also express features that increase malignancy, such as increased mobility and resistance to cell death. Both of these traits contribute to the endothelial mesenchymal transition that allows cancer cells to mobilize and form metastases.
Increased support from fibroblasts exposed to tobacco-caused larger tumors in a mouse model of cancer. Martinez-Outschoorn and colleagues also found a protein within these smoke-exposed fibroblasts that seemed to trigger these metabolic changes.
“The protein, called monocarboxylate transporter 4 (MCT4), is a major mechanism by which cigarette smoke exerts cancer aggressiveness, and we’ve shown how to manipulate and hopefully reverse it,” said lead author Marina Domingo-Vidal, a graduate student in Dr. Martinez-Outschoorn’s lab.
“We’ve also seen that smoke-exposed fibroblasts interact with other cells in the tumor stroma, such as the cells of the immune system. 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.”
Plans for Future Research
In a clinical trial that the team will be conducting, Curry hopes to inhibit this cancer-accelerating change induced from tobacco. Curry notes that their work is part of a growing body of research analyzing the relationship between various stromal cells and the tumor microenvironment. He hopes to target these stromal cells to improve outcomes in patients with cancer.
This trial will utilize a combination therapy consisting of two FDA-approved drugs, metformin and durvalumab. Metformin is a diabetes medication that will target the altered metabolism in the cancer cells and durvalumab serves to inhibit PD-L1, a checkpoint protein.
“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,” concluded Curry.
Research led by SKCC’s Dr. Ubaldo Martinez-Outschoorn showed that #cigarette smoke reprogrammed the cells surrounding cancer cells and helped drive head & neck squamous cell carcinoma aggressiveness: https://t.co/syxiUEhYWy via @MCR_AACR @ResearchAtJeff #HNSCC #hncsm pic.twitter.com/xiY4Qn3BQo
— Sidney Kimmel Cancer Center – Jefferson Health (@KimmelCancerCtr) August 8, 2019