Researchers identify therapeutic target for treating some kinds of cancer

Scientists at the São Paulo State Cancer Institute in collaboration with researchers elsewhere in Brazil and abroad are mapping how galectin-3 influences the progression of metastatic tumors.

By Elton Alisson

Agência FAPESP – An international group of researchers are unraveling the role played by a molecule called galectin-3 in the progression of some kinds of cancer.

The research is being done by scientists at the Cancer Translational Research Center of the São Paulo State Cancer Institute (ICESP) in collaboration with colleagues at the University of California, Davis, the Moffitt Research Center in Tampa, Florida, the University of Toronto, Canada, and the Ludwig Cancer Research Institute in São Paulo.

Some of the results of their studies, begun at the Center for Research on Cell-Based Therapy, one of FAPESP’s Research, Innovation and Dissemination Centers (RIDCs), were presented by Roger Chammas, head of ICESP’s Translational Research Center, to a session on cancer research during FAPESP Week UC Davis in Brazil.

Hosted by FAPESP and the University of California, Davis at Espaço APAS in São Paulo, the two-day event ending today (Wednesday, May 13) brings together scientists from UC Davis and institutions in São Paulo State to present research findings in a range of knowledge areas.

“Galectin-3 performs multiple functions. The molecule is expressed strongly enough to be detectable as a biomarker but it’s often missed in the evolution of some kinds of tumor,” Chammas told Agência FAPESP.

Galectin-3 is already used as a cardiac biomarker, Chammas explained. Increased expression of the molecule is an indication of potential heart failure, enabling at-risk individuals to be identified before the first symptoms appear.

In oncology, clinical studies by the Brazilian researchers and other groups elsewhere have found increased levels of galectin-3 in the blood plasma of patients with metastatic tumors. Metastasis occurs when secondary tumors form as cancerous cells spread through the bloodstream from a tumor located elsewhere in the body.

“Our research shows that expression of galectin-3 increases in the bloodstream of patients with different kinds of advanced-stage tumor, as in breast cancer or melanoma [skin cancer],” Chammas said. “Oddly enough, expression of this molecule in the tumor itself is low.”

A study conducted by the group in patients with glioblastoma, a central nervous system tumor, showed that galectin-3 accumulates in tumor cells with low oxygen and nutrient levels, boosting their survival and ability to migrate.

In melanomas, on the other hand, galectin-3 expression diminishes as the cancer progresses, even though it increases in the bloodstream. “Galectin-3 is involved in many biological processes,” Chammas said. “It’s not only a biomarker for various pathological states but also a target for therapeutic intervention.”

Multiple functions

One of galectin-3’s functions identified by the researchers is intensification of immune responses during the progression of metastatic tumors.

In some types of metastatic tumor, increased levels of galectin-3 expression can be interpreted as an emphatic danger alert, indicating that cells are able to escape the primary tumor and migrate to another tissue when conditions in the tumor microenvironment are adverse.

“Expression of the molecule increases especially in conditions of cell hypoxia, i.e. lack of oxygen, and nutrient deprivation,” Chammas explained.

“When galectin-3 itself can’t resolve this situation, the molecule eventually induces the formation of blood vessels and thereby enables the tumor to grow.” Because of galectin-3’s angiogenic capacity, i.e. its capacity to form blood vessels, alongside its various other functions, the molecule is now considered a potential therapeutic target.

But tumors do not depend continuously on galectin-3 to develop. “Our observations show that tumors need galectin-3 at specific times during their development,” Chammas said.

“The problem is knowing the right moment to intervene in the functions performed by galectin-3 during tumor progression, so that we know when to start and stop treatment of patients.”

Another problem, according to Chammas, is that because galectin-3 performs multiple functions during tumor progression it is not always useful to inhibit its expression as a therapeutic target.

“We need to identify precisely the right moment for intervention in the functioning of galectin-3 so as not to cause adverse effects in patients,” he said.

Molecular imaging

To obtain a better understanding of the functions performed by galectin-3 during well-defined specific phases of tumor progression, the research group at ICESP plan to intensify collaboration with researchers at UC Davis in molecular imaging studies of the tumor formation process.

The biomedical engineering group at UC Davis is considered one of the most experienced in the world in the use of molecular imaging, which enables scientists to visualize, characterize and measure biological processes at the molecular level in the cells of humans and other living systems.

“We expect to interact much more intensely with colleagues at UC Davis,” Chammas said. “They have very extensive experience in the use of different molecular imaging techniques, and can help us verify dynamic processes such as those we’ve observed with galectin-3 in real time.”

The Center for Molecular & Genomic Imaging (CMGI) was established at UC Davis in 2002 with state-of-the-art equipment to produce computed tomography, magnetic resonance, ultrasound and optical images, among others, for researchers at UC Davis and other institutions in the United States and elsewhere.

“The CMGI’s objectives include strengthening the university’s internal and external collaborations via the use of imaging in clinical trials and other applications. We also offer training opportunities for the next generation of radiochemists and scientists in the field of molecular imaging,” said Julie Sutcliffe, a professor at UC Davis’s Department of Biomedical Engineering, in her presentation.

According to Sutcliffe, action taken to remedy the shortage of radiochemists in the United States includes measures to attract more master’s, PhD and post-doctoral students.

“These initiatives afford major opportunities for collaboration with Brazil in this area,” Sutcliffe said.

In addition to Chammas and Sutcliffe, the session on cancer research was also addressed by Laura Marcu, who heads the UC Davis Biophotonics Laboratory, and Dirce Maria Carraro from A. C. Camargo Cancer Center.