Podcast: Artificial blood vessel visualizes cancer cell journey

Researchers from Johns Hopkins Institute for NanoBioTechnology are visualizing many of the steps involved in how cancer cells break free from tumors and travel through the blood stream, potentially on their way to distant organs.  Using an artificial blood vessel developed in the laboratory of Peter Searson, INBT director and professor of materials science and engineering, scientists are looking more closely into the complex journey of the cancer cell.

Figure 1. 3D projection of a confocal z-stack shows human umbilical vein endothelial cells (HUVECs) forming a functional vessel immunofluorescently stained for PECAM-1 (green) and nuclei (blue).

Figure 1. 3D projection of a confocal z-stack shows human umbilical vein endothelial cells (HUVECs) forming a functional vessel immunofluorescently stained for PECAM-1 (green) and nuclei (blue). (Wong/Searson Lab)

INBT’s science writer, Mary Spiro, interviewed device developer Andrew Wong, a doctoral student Searson’s  lab, for the NanoByte Podcast. Wong is an INBT training grant student. Listen to NANOBYTE #101 at this link.

Wong describes the transparent device, which is made up of a cylindrical channel lined with human endothelial cells and housed within a gel made of collagen, the body’s structural protein that supports living tissues. A small clump of metastatic breast cancer cells is seeded in the gel near the vessel while a nutrient rich fluid was pumped through the channel to simulate blood flow. By adding fluorescent tags the breast cancer cells, the researchers were able to track the cells’ paths over multiple days under a microscope.

VIDEO: Watch how a cancer cell approaches the artificial blood vessel, balls up and then forces its way through the endothelial cells and into the streaming fluids within the channel of the device. (Video by Searson Lab)

The lab-made device allows researchers to visualize how “a single cancer cell degrades the matrix and creates a tunnel that allows it to travel to the vessel wall,” says Wong. “The cell then balls up, and after a few days, exerts a force that disrupts the endothelial cells. It is then swept away by the flow. “

Wong said his next goal will be to use the artificial blood vessel to investigate different cancer treatment strategies, such as chemotherapeutic drugs, to find ways to improve the targeting of drug-resistant tumors.

Results of their experiments with this device were published in the journal Cancer Research in September.

Andrew Wong (left) and Peter Searson. (Photo by Will Kirk/Homewood Photography)

Andrew Wong (left) and Peter Searson. (Photo by Will Kirk/Homewood Photography)

Check out this gallery of images from the Searson Lab. The captions are as follows:
Figure 1. 3D projection of a confocal z-stack shows human umbilical vein endothelial cells (HUVECs) forming a functional vessel immunofluorescently stained for PECAM-1 (green) and nuclei (blue).
Figure 2. 3D projection of a confocal z-stack shows human umbilical vein endothelial cells (HUVECs) forming a vessel with dual-labeled MDA-MB-231 breast cancer cells on the periphery.
Figure 3. Phase-contrast and fluorescence overlays depicting a functional vessel comprised of human umbilical vein endothelial cells (HUVECs) with dual-labeled MDA-MB-231 breast cancer cells on the periphery (green in the nucleus, red in the cytoplasm).

 

 

What’s mechanics got to do with tissue development?

A recent study at Harvard, published in the journal Science, found that mechanical factors play a significant role in tissue development. Learning these factors that contribute to the natural formation of tissues will not only improve our understanding of tissues, it will also improve our ability to engineer tissues in the future and improve our ability to discern developmental problems.

Intestinal villi small http://goo.gl/DlKA7p

Intestinal villi small http://goo.gl/DlKA7p

The walls lining the intestines are not smooth. They are covered with many tiny, finger-like protrusions, or villi, yielding a high surface area for high nutrient absorption. These villi are present in many different animals including humans, chickens, and mice. This study follows the chick’s gut from earlier embryonic stages through the gut formation.

In the beginning of gut formation, the intestine is a smooth, cylindrical tube. As the embryo matures, a outer layer of smooth muscle binds the inner regions. The inner region continues to expand, but the outer region restricts it causing the inner tube to buckle and bend back over on itself. As the embryo continues to grow, the outer layer is enhanced and strengthened, causing the inners layers to make smaller and tighter folds, eventually yielding the villi. This paper shows that without the outer muscle layer, the inner layer will continue to grow, but rather than forming villi, it just ends up with a larger circumference.

This study goes on to show that across different animals (xenopus, chick, and mouse), while the time scales and intermediate steps may vary, the constraints from the outer loop cause the buckling of the inner layer into the villi.

This research establishes that in natural formation of specific tissues—and consequently engineered tissues—mechanical factors must not be ignored.

Villification: How the Gut Gets Its Villi 

Charli Dawidczyk is a PhD candidate in Materials Science and Engineering working in Peter Searson’s research group.

 

Unlocking the mysteries of the blood-brain barrier

It might astonish you to know that, although we use our brains all the time, science knows very little about how they actually work. That is why recently, President Barack Obama announced a $100 million initiative to map the human brain.

“We can identify galaxies light-years away; we can study particles smaller than an atom; but we still haven’t unlocked the mysteries of the three pounds of matter that sits between our ears,” Obama said in a press conference on the announcement April 2.

The blood-brain barrier involves functional interactions between endothelial cells that form brain capillaries, astrocytes, and pericytes in a complex microenvironment. (Illustration by Martin Rietveld)

The blood-brain barrier involves functional interactions between endothelial cells
that form brain capillaries, astrocytes, and pericytes in a complex microenvironment. (Illustration by Martin Rietveld)

Obama’s Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) project will seek to discover what occurs between the 100 billion cells firing inside the brain with the goalof helping to prevent and even cure neurological diseases, such as Alzheimer’s or Parkinson’s, that affect as many as 100 million Americans.

Johns Hopkins University is at the forefront of brain science research. The Brain Science Institute (BSi) at the Johns Hopkins School of Medicine was launched to develop new multidisciplinary research teams; create cutting edge-research cores for use by all brain researchers at Hopkins; and foster translation of discoveries to treatments of brain diseases, in part, by improving our ability to partner with industry and biotechnology.

In 2012, Peter Searson, professor of materials science and engineering and director of Johns Hopkins Institute for NanoBioTechnology (INBT), joined forces with Jeffrey Rothstein MD, PhD, director of the BSi, to create the Blood-Brain Barrier Working Group. This group brings together researchers with diverse interests and expertise to address key problems associated with drug delivery, to discover the role of the blood-brain barrier (BBB) in disease, and to elucidate the structure and function of the BBB.

“The blood-brain barrier is a dynamic interface that separates the brain from the circulatory system and protects the central nervous system from potentially harmful chemicals while, at the same time, regulating transport of essential molecules and maintaining a stable environment,” Searson said. “It is formed from highly specialized endothelial cells that line the brain capillaries, which transduce signals in two directions: from the vascular system and from the brain. The structure and function of the BBB is dependent upon the complex interplay between different cell types, specifically the endothelial cells, astrocytes and pericytes, within the extracellular matrix of the brain and with the blood flow in the capillaries.”

Although the BBB serves the important purpose of tightly regulating the environment of the brain and preventing sudden changes, which the brain cannot tolerate, Searson said, “this interface also blocks the passage of drug molecules to treat disease, neurodegenerative disorders, inflammation or stroke. Unfortunately, animal models are insufficient for use in under-standing how the human blood-brain barrier functions or responds to drugs. In addition, little is known about how disease, inflammation or stroke disrupts or damages the blood-brain barrier.”

With this in mind, the BBB working group has two primary goals, Searson explained. “Our long-term goal is to build an artificial microvessel that will be the first platform that recapitulates a brain capillary in its local microenvironment. This will enable fundamental studies as well as drug discovery and the development of methods to cross the blood-brain barrier,” Searson said.

The second goal is to understand how the blood-brain barrier can be damaged or disrupted so that strategies can be developed to repair it. Injury and disease can disrupt the normal structure and function of the blood brain barrier.

Currently the BBB Working Group has 40 researchers from disciplines as diverse as anesthesiology, materials science and engineering, pharmacology and oncology. Three postdoctoral fellows and 12 pre-doctoral students are also involved. The group meets monthly and hosts expert speakers on various topics. The working group website also lists current funding opportunities to which members can apply and conferences and workshops of interest.

Membership in the working group is open to any student, faculty member or staff at Johns Hopkins University in any discipline.

Visit the Blood-Brain Barrier Working Group website here.

This article was written by Mary Spiro and appeared in the 2013 issue of Nano-Bio Magazine.

Podcast: Nanotech method to study cell detachment could lead to improved cancer therapies

Peter Searson

Peter Searson

Cancer spreads from organ to organ when cells break free from one site and travel to another. Understanding this process, known as metastasis, is critical for developing ways to prevent the spread and growth of cancer cells. Peter Searson, Reynolds Professor of Materials Science and Engineering in the Whiting School of Engineering and director of the Institute for NanoBioTechnology, led a team of engineers who have developed a method to specifically measure detachment in individual cells.

The method, which uses lab-on-a-chip technology, allows researchers to observe and record the exact point when a cell responds to electrochemical cues in its environment and releases from the surface upon which it is growing. Better knowledge of the biochemistry of cell detachment could point the way to better cancer therapies. In this “Great Ideas” podcast, Elizabeth Tracey, communications associate for the School of Medicine, interviews Searson about this current research.

“…We know that processes like cell detachment are important in cancer metastasis, where cells become detached from tumors…” Peter Searson

Click here to listen:  Great Ideas Podcast: Peter Searson

Related links:

You can watch a video and read more about Searson’s method of studying cell detachment here.

Peter Searson’s INBT profile page.

This podcast was originally posted to the Johns Hopkins University “Great Ideas” web page. To view the original posting, click here.