University of Texas at Dallas researchers studied the effects of a ketogenic diet on mice genetically engineered to develop lung cancer that closely mimics human cancer. The mice develop both squamous cell carcinoma (green) and adenocarcinoma (red). Researchers found that in mice fed the keto diet (left), growth of squamous cell lung cancer was suppressed, while adenocarcinoma was unaffected by the diet. Lung tissue from a mouse fed a normal diet is shown at right. [University of Texas at Dallas]

The results of newly reported studies in mice and humans suggest that restricting blood glucose levels through diet or by using existing drugs may help to increase the effectiveness of current treatments for multiple types of cancer. An international team of scientists headed by researchers at the University of Texas (UT) at Dallas found that feeding mice a very low sugar, ketogenic diet, and giving the animals an existing anti-diabetic diabetes drug slowed the progression of squamous cell carcinoma (SCC) lung tumors. The anticancer effects were specific to SCCs, and glucose-restrictive measures had no effect on non-SCC-type tumors including adenocarcinomas.

The team, including researchers across the United States, and in Korea and Japan, also found a strong link between blood glucose levels and survival in human patients with SCCs specifically, which “further implicates the potential efficacy of glucose restriction in attenuating squamous cell cancer growth,” commented Jung-Whan “Jay” Kim, PhD, an assistant professor of biological sciences at UT Dallas. “The key finding of our new study in mice is that a ketogenic diet alone does have some tumor-growth inhibitory effect in squamous cell cancer. When we combined this with the diabetes drug and chemotherapy, it was even more effective.”

Kim is corresponding author of the researchers’ published paper in Cell Reports, which is titled, “p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas.”

There are relatively few therapeutic options for squamous cell tumors, and the newer, targeted molecular therapies are generally not proving effective for this type of cancer. “SCC is a major class of malignancy arising from squamous cells of the epithelia and is responsible for more than one million cancer deaths annually worldwide,” the authors wrote. “ … decades old platinum-based chemotherapy or radiation regimens still remain the first-line treatment options and thus, retain limited specificity to the unique characteristics of SCC.”

Scientists suspect that many different types of cancer may be heavily dependent on glucose as their energy supply, and prior laboratory studies by Kim’s researchers had demonstrated that SCCs, in particular, may be more dependent on glucose than are other cancer types, such as adenocarcinomas. Interestingly, most SCCs share common genetic alterations, including amplification of chromosome 3q, which contains key transcription regulators p63 and SOX2. Collective research indicates that these transcription factors may cooperate to promote SCC, “the reliance on which may present a targetable vulnerability,” the investigators stated.

Increased glycolysis—this is the first step in the breakdown of glucose to release energy—is thought to support cancer progression by helping the cancer cells meet their high energy demands. But increasing evidence also indicates that different cancer types may have different requirements for glucose metabolism. “For example, our recent study demonstrated a distinct metabolic heterogeneity between two subtype tumors of non small-cell lung cancer (NSCLC), lung squamous cell carcinoma (LSCC), and lung adenocarcinoma (LADC),” the researches commented. “LSCC exhibits distinctively elevated glucose transporter 1 (GLUT1) expression resulting in a high reliance on glucose, whereas LADC is significantly less dependent on glucose for survival and tumor growth.”

GLUT1 is a transporter protein that is involved in shuttling glucose across the plasma membrane into cells. As part of their newly reported research, the authors’ analysis of existing human cancer gene expression data and tests on human cancer tissue samples indicated that GLUT1 was exclusively upregulated in SCCs. “Collectively, these results uncovered remarkably heightened GLUT1 upregulation as a potent and unique metabolic characteristic embedded in squamous lineage cancer,” they wrote. The combined results of experiments in cell lines demonstrated that GLUT1 expression is regulated by p63 and SOX2 cooperatively, resulting in increased GLUT1 expression in SCC, and so upregulated glycolysis.

Given SCC’s dependence on glycolysis, the researchers wondered whether restricting tumor cell access to glucose could have an anticancer effect. “Given the strict reliance of SCC on glucose for sustaining antioxidative capacity and survival, we reasoned that SCC might be highly susceptible to glucose restriction.” They found that the growth of lung and esophageal SCCs in tumor-bearing mice was held back when animals were fed a ketogenic diet (with just 0.1% carbohydrate). In contrast. the ketogenic diet had no effect on the growth of lung and esophageal adenocarcinomas.

While the ketogenic diet did hold back growth of SCCs, it didn’t lead to tumor regression, so the researchers next treated tumor-bearing animals with chemotherapy in addition to dietary glucose restriction. This dual approach was more effective at holding back tumor development than either ketogenic diet or chemotherapy alone, and had no adverse effects.

They then tested a pharmacologic approach to restricting blood glucose levels, using an FDA-approved anti-diabetic SGLT2 inhibitor, which blocks glucose reabsorption into the kidneys. As hoped, squamous cell tumor-bearing animals treated with the drug showed reduced tumor growth, although, again, there was no effect of treatment on tumor burden or overall survival.  And when the researchers knocked down the SLC2A1 gene that codes for GLUT1 in experimental mice, the result was again “dramatically decreased SCC tumors,” which added further weight to the suggestion that GLUT1 plays pivotal roles in SCC tumorigenesis. “Collectively, these results support our model that glucose restriction can be an effective therapeutic strategy for SCC tumors,” the researchers commented.

In a final series of investigations the team used statistical tools to examine the relationship between blood glucose levels and survival in 192 patients with either lung or esophageal SCC, and 120 patients with lung adenocarcinoma. The results highlighted a “robust correlation” between high blood glucose measurements and poor survival rate in lung and esophageal SCC patients, but not among the lung adenocarcinoma patients. “Surprisingly, we found a robust correlation between higher blood-glucose concentration and worse survival among patients with squamous cell carcinoma,” Kim said. “We found no such correlation among the lung adenocarcinoma patients. This is an important observation that further implicates the potential efficacy of glucose restriction in attenuating squamous-cell cancer growth.”

The authors say their collective results point to “a previously unrecognized metabolic reliance and vulnerability distinctively embedded across all SCCs, in which the major glucose transporter GLUT1 is exceptionally overexpressed through the squamous lineage-specific transcriptional network, p63 and SOX2 … Enhanced GLUT1 expression is linked to an exquisite reliance on glucose for survival and tumor growth in SCC.”

They acknowledge that further, more comprehensive and detailed clinical studies will be needed to validate the findings, but suggest that restricting glucose could represent a new therapeutic approach against squamous cell tumors. “This study presents a viable and potentially rapidly translatable treatment paradigm in targeting squamous cancers precisely not by direct inhibition but modulating metabolism at a systemic level.”

As Kim added, “Manipulating host glucose levels would be a new strategy that is different from just trying to kill cancer cells directly … I believe this is part of a paradigm shift from targeting cancer cells themselves … Maybe we can manipulate our own biological system a little bit or activate something we already have in place in order to more effectively combat cancer … Immunotherapy is a good example of this, where the human immune system is activated to go after cancer cells.”

 

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