Molecule found on cancer cell surfaces may lead to new therapies

Researchers at the Federal University of São Paulo (UNIFESP) in Brazil have identified a molecule on the surface of cells that could be a promising therapeutic target against cancer. This molecule plays an important role in tumor progression by regulating cellular behavior. The research is published in the journal Cytotechnology.

The work showed that overexpression of the syndecan-4 (SDC4) receptor provides tumor cells with a protective shield. In a laboratory experiment, the researchers silenced the receptor and halted the accelerated growth of tumor cells, causing them to resume responding to natural programmed cell death mechanisms.

Our study shows that SDC4 could become a promising therapeutic target and serve as a diagnostic marker for monitoring disease progression. The strategy of silencing this molecule has the potential to prevent the proliferation of cancer cells, but we’re still in the early stages of research and need to validate the results for each specific case of the disease,” said Carla Cristina Lopes, full professor in the Department of Biological Sciences at UNIFESP and lead author of the study.

How tumor cells evade death

Lopes explained that under normal conditions, cells express the SDC4 macromolecule for essential functions, such as signaling and adhering to other cells and tissues. However, changes in SDC4 expression, or when a cell produces an excessive amount of the macromolecule, are associated with the development and progression of cancer.

“Syndecan-4 protects tumor cells from a specific type of cell death called anoikis, which occurs when a cell detaches from tissue,” Lopes explained.

She said that for cells to form tissues, they need to be anchored—that is, “glued” to one another and to the extracellular matrix, a kind of filler between cells. Thus, when a normal cell detaches from tissue, it activates a self-destruction mechanism called anoikis, a Greek term meaning “death by homelessness.”

In cancer, however, this process is subverted, and the most aggressive tumor cells can survive and migrate through the bloodstream until they colonize other organs (metastasis).

“What is metastasis? Metastasis is simply that tumor-forming cell that leaves a tissue and enters the bloodstream until it invades other tissues. That happens because these cells manage to circumvent anoikis, a form of cell death caused by loss of adhesion to their substrate,” Lopes explained.

Silencing SDC4 reversed malignancy

In experiments conducted on adherent aortic endothelial cells from rabbits cultured in a laboratory setting, the researchers observed that fewer than 5% survived disruption of adhesion and remained alive in suspension. This small group, however, became highly aggressive and exhibited SDC4 overexpression. When the researchers silenced the molecule using genetic engineering techniques, the cells lost their malignant properties and became dependent on adhesion to survive once again.

“This reversal significantly increased programmed cell death and reduced the invasive capacity of the cells, making SDC4 a promising therapeutic target for stopping metastasis before it begins,” Lopes said.

The research also showed that the mechanism of action of SDC4 involves modulating the cell cycle as early as its initial phases.

“When we silenced SDC4, there was an increase in an inhibitor of cell division [p27] that acts early in the cell division process [G1 phase] by blocking uncontrolled proliferation. In addition, there was regulation of the expression of cyclin and CDK [cyclin-dependent kinase], which are regulators of cell cycle progression,” Lopes said.

The study on the role of SDC4 in cell cycle modulation resulted in the master’s dissertation of first author Bianca Zaia F. Ferreira.

CBD is the next question

After describing the role of SDC4 in the survival and aggressiveness of tumor cells, the researchers at UNIFESP are now investigating whether cannabidiol (CBD) can act on SDC4 molecules.

“The discovery of the role of SDC4 in metastasis paves the way for a series of new studies. One of our lines of investigation is to verify whether cannabidiol can reverse the malignant behavior of anoikis-resistant cells by modulating SDC4 expression or interfering with the signaling pathways that sustain uncontrolled growth. It would be an interesting approach, but we’re still in the early stages of investigation,” Ferreira said.

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Stephanie Baum

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Robert Egan

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