New Biomarker Recognized For Colorectal Cancers

Ceramides are cell-membrane-dwelling sphingolipids involved in cellular signaling and maintaining the molecular structural stability of cell membranes. They are involved in inflammation, cell-cycle arrest and apoptosis, and play suspected roles in cancers (particularly colorectal cancers), autoimmune diseases, Alzheimer’s disease, and heart disease.

Ceramides can be detected in malignant tissue, cerebrospinal fluid, and circulating blood, and are therefore emerging as potentially important diagnostic, staging, and treatment-monitoring colorectal cancer (CRC) biomarkers, but it is unclear whether ceramides drive oncogenesis or are instead modulated by inflammation or other pathogenic processes.

A recent study found that expression of the oncogenic signal transducer lactosylceramide synthase β-1,4-galactosyltransferase-V (β-1,4-GalT-V) is increased in CRC tumor tissues compared to healthy tissues. Using reverse transcription polymerase chain reaction (RT-PCR), immunohistochemical staining and ELISA assays, the researchers confirmed that inhibiting glycosphingolipid synthesis with a ceramide analog, D-PDMP, decreased β-1,4-GalT-V levels and inhibited CRC cell proliferation. 

“We conclude that β-1,4-GalT-V may serve as a diagnostic and therapeutic biomarker for the progression of human colorectal cancer, and consequently, inhibition of glycosphingolipid synthesis may be a novel approach for the treatment of this life-threatening disease,” said lead study author Subroto B. Chatterjee, MD, of Johns Hopkins University Hospital’s Pediatrics and Medicine Department in Baltimore.

Based on previous preclinical research, the study authors had suspected β-1,4-GalT-V to be involved in human CRC tumor cell proliferation, Chatterjee told Cancer Network. They assessed CRC tissue biopsy samples’ immunoreactivity to β-1,4-GalT-V antibodies and measured tumor tissues’ β-1,4-GalT-V and glycosphingolipid levels, and β-1,4-GalT-V mRNA levels.

All of these markers were “markedly increased” in the CRC samples, Chatterjee said.

“β-1,4-GalT-V immunostaining of the cytoplasm, both in control and colorectal tumor tissues, suggested that β-1,4-GalT-V must exist in a membrane-bound as well as a soluble form,” Chatterjee noted. “Solubility would enable measurement of this antigen in various body fluids via noninvasive or minimally-invasive procedures.”

In previous work with mice, the team found that D-PDMP therapy diminished kidney tumor volumes by more than 50% after four weeks. The new findings bolster that earlier work’s suggestion that tumor progression can be countered by inhibiting glycosphingolipid synthesis, Chatterjee said. “Inhibition of glycosphingolipid synthesis might be a novel approach for treating human colorectal cancers-and possibly other types of cancer,” he said.

A β-1,4-GalT-V and lactosylceramide-based biomarker “liquid biopsy” test could complement TP53, NMT1 and APC-based gene-panel biomarker tests to improve diagnostic accuracy, he believes.

It remains unclear whether or not ceramide biomarkers can differentiate between cancers, autoimmune diseases, diabetes, and other diseases with which their increased production is associated.