The transformation of healthy cells into invasive colorectal tumors is an extraordinarily complex process involving numerous molecular mechanisms, according to cancer biologists in China who have discovered that low levels of a single enzyme strongly influence the pathway to malignancy.

Scientists worldwide have been on the hunt for overlooked and underappreciated biological pathways involved in the tumorigenesis of one of the most common forms of cancer. The team of researchers in China who have uncovered the latest one underscore that possibly others remain to be found.

Colorectal cancer—CRC—is the third leading form of cancer around the world, and while usually associated with older age, the disease is inexplicably increasing among people under the age of 50, a trend particularly evident in the United States. A 2023 American Cancer Society study found that 20% of CRC diagnoses in 2019 involved people under the age of 55, double the rate of 1995. In the same study, rates of advanced disease increased by 3% in people under 50.

Regardless of the age when the cancer is diagnosed, oncologists say the most common risk factors are physical inactivity; obesity; low consumption of dietary fiber; smoking; family history of CRC or colon polyps; inflammatory bowel disease; certain genetic conditions, such as Lynch syndrome, and excessive alcohol consumption.

Scientists in the department of colorectal surgery at the Sixth Affiliated Hospital of Sun Yat-sen University in Guangdong have taken a new look at how CRC emerges. Working with collaborators elsewhere in China, they have found that a critical enzymatic imbalance may drive tumor formation in colorectal cancer.

Reporting in Science Translational Medicine, the team highlighted an enzyme named GPT1, which stands for glutamic-pyruvic transaminase 1. Colorectal cancer, the researchers asserted, is characterized by decreased amounts of GPT1, a metabolic enzyme with apparent functions in cancer progression.

Lead author of the study, Li Xiong, along with a large team of co-investigators, confirmed decreased GPT1 in CRC patients and demonstrated in a series of experiments that low expression of GPT1 was associated with worse CRC prognoses. The researchers were able to define the role of GPT1 in colorectal cancer by tracing the progression of the disease from normal cell to pre-cancerous cell to full-blown malignancy. The team was able to deduce the importance of GPT1 in CRC by noting its diminishing levels as the disease progressed.

“The tumorigenesis of colorectal cancer—CRC—often follows the normal-adenoma-carcinoma—N-A-C—sequence,” Xiong writes in the study.

Even though the molecular mechanisms underlying colorectal adenoma carcinogenesis remain largely unknown, the Guangdong team was able to define a causative role for low GPT1. “We analyzed transcriptomic profile changes in normal, advanced adenoma, and carcinoma tissues from patients with CRC,” Xiong added, noting that as the disease progresses GPT1 is down-regulated, meaning the enzyme and, hence, its activity dramatically declined.

The study also revealed that a compound by the name of poliumoside, which activates GPT1, can suppress tumor growth, suggesting that poliumoside could be translated into a new therapy for CRC, allowing a potentially new method of tumor suppression.

As the third most common form of cancer, CRC in advanced stages still has poor survival rates, a factor that underscores the need for new treatments. Because these tumors develop from precancerous adenomas in the colon lining, medical investigators, such as Xiong and colleagues, have been searching for common molecular changes between the precancerous and cancerous stages.

It is well known that adenomas accumulate genetic mutations and undergo shifts in metabolism that destabilize them along the pathway to malignancy. However, scientists still haven’t identified all of the molecular mechanisms that shape the transformational pathway to CRC. The identification of GPT1 is a step toward pinpointing one of multiple steps involved in tumorigenesis of colorectal cancer.

“About 85% of CRCs arise from adenomas, and advanced adenomas are considered the major precancerous lesions leading to colorectal carcinogenesis,” Xiong explained in the study. “An increased rate of adenoma detection is associated with a reduction in the risk and mortality of CRC, highlighting the importance of early detection and removal of precancerous lesions.”

Xiong underscored that some patients who have had adenomas removed still have an increased risk of developing new adenomas or CRC. To monitor adenoma growth, the US Multi-Society Task Force on CRC and the European Society of Gastrointestinal Endoscopy recommend colonoscopy surveillance three years after removal of an advanced adenoma equal to or greater than 10 millimeters in size. Adenomas of this size suggest a potentially high risk of CRC development.

“Nevertheless, effective indicators to accurately evaluate the risk of adenoma transformation are still lacking,” Xiong argued, “making it difficult to ensure that high-risk patients receive timely intervention and low-risk patients avoid unnecessary colonoscopies. Therefore, it is important to elucidate the molecular mechanisms of colorectal adenoma carcinogenesis.”

To better understand the role of GPT1, the Guangdong team examined normal colorectal tissues, adenomas, and tumor tissues from patients with colorectal cancer. The samples showed a marked lack of GPT1, the deficiency of which also correlated with poorer clinical outcomes. Studying cells and animal models in the lab, the authors then showed that GPT1 normally suppressed the formation of tumors from adenomas by producing a metabolic molecule named α-ketoglutarate, which inhibited the WNT signaling pathway, disrupting the metabolically important folate cycle.

Regarding poliumoside, the team of cancer biologists found that it reactivated GPT1 and slowed the growth of tumors. Tumor growth was slowed in patient-derived organoids and mouse models of colorectal cancer, indicating the compound should be tested in clinical trials.

“In this study, we identified GPT1 as a regulator involved in metabolic reprogramming and the initiation and progression of CRC,” Xiong concluded. “Deficiency of GPT1 promoted CRC tumorigenesis by rewiring cellular metabolism in enzyme-dependent and enzyme-independent ways.”

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