Alterations of Little-Known Layer Covering Cell Membranes Promotes Mechanical Forces Leading to Metastasis
A research team led by UC San Francisco scientists has shown that cancer-induced structural changes in a sugary coating ensheathing cells can promote mechanical interactions that fuel tumor growth and metastasis.
Every introductory biology class teaches that cells are enclosed by a membrane, but it is less well known that the cell membrane is itself covered by the glycocalyx (meaning “sugar coat”), a layer of sugar compounds called glycans.
Though the diverse functions of the glycocalyx are only beginning to be understood, scientists know that its biochemical composition undergoes predictable changes during embryonic development, in cancer, and when stem cells differentiate into particular cell types.
The new research, published June 25, 2014 in Nature, was led by Matthew J. Paszek, PhD, now assistant professor of chemical and biomolecular engineering at Cornell University, who conducted the work as a postdoctoral associate at UCSF's Center for Bioengineering and Tissue Regeneration, a laboratory directed by senior author Valerie M. Weaver, PhD.
The group first analyzed tumor cells from cancer patients, some of whom had metastases at sites distant from their original tumor. The tumor cells from patients with metastatic cancer were seen to have a preponderance of genes coding for “bulky” glycans that would significantly increase the thickness of the glycocalyx on those cells.
To decipher whether that bulkiness might somehow drive cancer aggressiveness and metastasis, the researchers devised a computer model to test the biomechanical consequences of a thicker glycocalyx.
Not surprisingly, they found that a bulkier glycocalyx would tend to reduce the overall interactions between cells and the extracellular matrix (ECM), the molecular scaffolding that holds cells together to form tissues, much of which is mediated by membrane-bound proteins called integrins.
But the model also predicted that integrins that did manage to bind with the ECM would create a “kinetic trap” that would funnel additional integrins to that same site, putting integrin signaling into overdrive wherever the cell adhered to the ECM.
When activated, integrins trigger pathways involved in cell growth, cell division, and cell death, all of which are disrupted in cancer, so the mechanical hypothesis of aggressive cancer growth generated by the researchers’ computer model made sense.
According to Weaver, the kinetic trap in the bulky glycocalyx of cancer cells could act as a sort of “all or none” switch: in a bulky glycocalyx, integrin binding and activation is generally less likely, but when it occurs it is decisive. This switching behavior is desirable in stem cells, which have a very bulky glycocalyx, said Weaver, who is also a professor of surgery and anatomy at UCSF. “You don’t want every and any bound receptor to activate a stem cell. Mostly you want nothing to happen. But when you do get the right sort of trigger, you want go, go, go.”
The group decided to put this idea to the test in real cells, first covering the surface of non-malignant breast cells with “glycomimetics,” synthetic glycans with the bulky properties they had identified in cancer patients. Using advanced microscopic techniques they found that integrins indeed spontaneously clustered together, just as the model had predicted.
An additional set of experiments with glycomimetics showed that a bulky glycocalyx may be a “double whammy” in cancer: in addition to increasing integrin signaling due to clustered binding to the ECM, the bulky glycans themselves were seen to exert forces on integrins that keep them in an activated state.
The scientists brought the study full-circle by examining tumor cells circulating in the blood of patients with advanced breast cancer, and they found that the cells’ glycocalyx was comprised of high levels of bulky glycans.
Weaver and Paszek were joined in the research by scientists from UC Berkeley; The University of Bordeaux, France; Lawrence Berkeley National Laboratory; The Florida State University; and The University of Pennsylvania. This work was supported by the Kavli Institute at Cornell for Nanoscale Science; the UCSF Program for Breakthrough Biomedical Research; the U.S. Department of Defense Breast Cancer Research Program; the National Institutes of Health; the French Ministry of Research; the French National Center for Scientific Research; The French National Research Agency; INSERM, Fondation ARC pour la Recherchesur le Cancer; Conseil Régional d’Aquitaine; and The Breast Cancer Research Foundation.
UCSF is the nation’s leading university exclusively focused on health. Now celebrating the 150th anniversary of its founding as a medical college, UCSF is dedicated to transforming health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with world-renowned programs in the biological sciences, a preeminent biomedical research enterprise and two top-tier hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital San Francisco.