Princeton scientists discover an interaction that helps cancers spread to bone

April 15, 2019

A Princeton-led team of researchers have discovered a factor that promotes the spread of cancers to bone, opening the way toward treatments that could mitigate cancer's ability to colonize bone. The study by Mark Esposito, Yibin Kang and colleagues appears in the April 15 issue of Nature Cell Biology.

"A large majority of human cancers are carcinomas derived from epithelial cells," says Kang, a professor of molecular biology and the corresponding author of the paper. Carcinomas grow from a single mutated cell into a tumor, a solid mass of cancerous cells. As long as it remains contained at its site of origin, a tumor may disrupt the function of its host organ, but it only indirectly affects the rest of the body. However, cancers will often metastasize -- that is, spread -- to colonize other, distant tissues. Breast cancers, for example, commonly metastasize to lung, liver, brain and bone. Patients whose tumors have metastasized suffer greater systemic disruption and are much less likely to achieve a successful cure. Most deaths from cancer occur after metastasis, so it is important to understand what signals control or promote this process. Kang's team examined the motility, or ability to move, of the epithelial cells that line the surfaces within the body, including skin, organs and blood vessels.

"Epithelial cells are normally not motile, but cancer cells undergo a process called epithelial-mesenchymal transition, or EMT, to become more migratory and escape from the primary tumor," explained Kang. "Once they reach a distant organ, they must then go through the reverse process, mesenchymal-epithelial transition, or MET, to revert to the epithelial state in order to proliferate and form a metastatic colony."

Although EMT is well studied, the signals that drive MET are still poorly understood. It's thought that MET is triggered by interactions between surface proteins on cancer cells and corresponding ligands or receptors found on the cells that naturally reside in the tissue being colonized. While studying signals that drive cancer metastasis and MET in bone, the Princeton researchers' attention was drawn to an adhesion molecule called E-selectin.

E-selectin is found on the cells that line capillaries throughout the body, where it aids in recruitment of immune cells from blood during inflammation by giving them something to latch onto. It has long been suspected that E-selectin may facilitate the recruitment of cancer cells to secondary organs in a similar manner during metastasis, but no evidence of this has yet been found. In fact, mice lacking E-selectin entirely are not protected from lung colonization by breast cancer cells. This may be partly due to the distribution of E-selectin; the researchers found that E-selectin is more strongly expressed in bone vasculature than in the lung. Accordingly, they observed that mice lacking E-selectin are less susceptible to bone metastasis than are normal animals. Importantly, however, E-selectin in bone is a prominent part of the environmental niche that supports the early differentiation and growth of specialized immune cells and blood cells.

"Our study shows this environment is hijacked by metastasizing cancer cells so that E-selectin nurtures the cancer cells in their early phases of growth," said Esposito, a postdoctoral fellow in Kang's lab and the lead author on the group's paper.

"What we found in this study is when tumor cells bind to bone vascular E-selectin, they undergo MET, and at the same time exhibit elevated signaling through the Wnt pathway, to enhance their cancer stem cell properties and promote new tumor growth," said Kang.

How does bone E-selectin stimulate these responses in cancer cells?

"E-selectin binding requires special modification of its ligand by a unique type of sugar decoration catalyzed by a family of enzymatic proteins," says Kang. Binding of E-selectin to this specially modified protein on the cancer cell is what stimulates MET and supports the cancer cell's growth. The identity of this ligand is still unknown, so further research on this subject is needed.

Regardless of its identity, it's already clear that this ligand strongly influences cancer outcomes. Analysis of human breast cancer cohorts showed that elevated expression of proteins that perform the sugar modification is associated with a greater chance of metastatic relapse. Furthermore, the researchers identified the protein Glg1, which they think may aid in the ligand's maturation or surface expression, as a prognostic marker for bone metastasis. These findings presented a tantalizing possibility: that interfering with the ability of the ligand to interact with E-selectin might reduce bone metastasis.

To investigate this, Kang's group used a drug called Uproleselan, a sugar-mimetic compound that blocks E-selectin binding.

Experiments with Uproleselan showed that it significantly reduces bone metastasis and confers a survival advantage on mice injected with human breast cancer cells.

"Although still untested in the clinic, the mouse experiments done in this study show the therapeutic benefit of such ... compounds to reduce bone metastasis," said Kang.
-end-
"Bone Vascular Niche E-selectin Induces Mesenchymal-Epithelial Transition and Wnt Activation in Cancer Cells to Promote Bone Metastasis," by Mark Esposito, Nandini Mondal, Todd Greco, Yong Wei, Chiara Spadazzi, Song-Chang Lin, Hanqiu Zheng, Corey Cheung, John Magnani, Sue-Hwa Lin, Ileana Cristea, Robert Sackstein and Yibin Kang, appears in the April 15 issue of Nature Cell Biology (DOI: 10.1038/s41556-019-0309-2). The research was funded by grants from the National Institutes of Health (F31CA192461, R01CA141062 and NHLBI PO1 HL107146), the New Jersey Commission for Cancer Research, the Program of Excellence in Glycosciences, the Team Jobie Fund, the Susan G. Komen Foundation (SAC160067), Glycomimetics Inc., the Brewster Foundation and the Department of Defense (BC123187). This research was also supported by the Preclinical Imaging, Genomic Editing and Flow Cytometry Shared Resources of the Rutgers Cancer Institute of New Jersey (P30CA072720).

Princeton University

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.