N-linked oligosaccharide processing and autocrine stimulation of tumor cell proliferation

I VanderElst1, J W Dennis

  • 1Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada.

Insights

Branched N-linked oligosaccharides are crucial for cancer cell growth and metastasis. Inhibiting their processing slows tumor growth in vitro and in vivo, suggesting a therapeutic target for reducing cancer progression.

Area of Science:

  • Cancer Biology
  • Glycobiology
  • Tumorigenesis

Background:

  • Somatic mutations affecting N-linked oligosaccharide processing and chemical inhibitors can reduce tumor metastasis.
  • Complex N-linked oligosaccharides are common in malignant cells and may play a role in tumor progression.

Purpose of the Study:

  • To investigate the role of branched complex-type N-linked oligosaccharides in the growth and metastatic potential of MDAY-D2 tumor cells.
  • To determine if impaired oligosaccharide processing affects autocrine growth factor signaling and in vivo tumor growth.

Main Methods:

  • Generation and characterization of glycosylation mutants of the MDAY-D2 cell line.
  • Assessment of cell growth rates in serum-free medium (SFM) and serum-containing medium.
  • Treatment with the N-linked processing inhibitor swainsonine.
  • Analysis of autocrine growth factor activity in conditioned medium.
  • Correlation of in vitro growth rates with in vivo subcutaneous tumor growth.

Main Results:

  • Glycosylation mutants with truncated or less branched N-linked oligosaccharides exhibited slower growth in SFM but not in serum-containing medium.
  • Swainsonine treatment reduced cell growth in SFM, and both mutants and swainsonine-treated cells showed reduced responsiveness to autocrine growth factors.
  • In vivo tumor growth rates correlated with in vitro growth rates in SFM.

Conclusions:

  • Branched complex-type N-linked oligosaccharides are essential for optimal autocrine-dependent growth of MDAY-D2 cells in SFM.
  • These oligosaccharides are required for efficient response to autocrine growth factors.
  • The findings suggest that branched N-linked oligosaccharides are a significant factor in tumor progression in vivo.

Related Concept Videos

Autocrine Signaling01:01

Autocrine Signaling

Autocrine signaling is one of the many signaling mechanisms that function inside multicellular organisms to carry out intercellular communication. In this type of signaling mechanism, the same cell that secretes an extracellular signaling molecule also expresses the receptors to bind and respond to that signaling molecule.
Autocrine Signaling in Macrophages
Under normal physiological conditions, autocrine signaling is essential for maintaining homeostasis. This process is well characterized in...
Protein Glycosylation01:25

Protein Glycosylation

Glycosylation, the most common post-translational modification for proteins, serves diverse functions. Adding sugars to proteins makes the proteins more resistant to proteolytic digestion. Glycosylated proteins can act as markers and receptors to promote cell-cell adhesion. Additionally, they have many essential quality control functions in the cell, such as correct protein folding and facilitating transport of misfolded proteins to the cytosol, which can be degraded.
Glycosylation occurs in...
Oligosaccharide Assembly01:24

Oligosaccharide Assembly

Protein glycosylation starts in the ER lumen and continues in the Golgi apparatus. Glycosyltransferases catalyze the addition of sugar molecules or glycosylation of proteins. Usually, these enzymes add sugars to the hydroxyl groups of selected serine or threonine residues to form O-linked glycans or the amino groups of asparagine residues to form N-linked glycans. Different positions on the same polypeptide chain can contain differently linked glycans.
Multiple sugar molecules that may or may...
The Tumor Microenvironment02:17

The Tumor Microenvironment

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
Biosynthesis of Polysaccharides01:26

Biosynthesis of Polysaccharides

Polysaccharides such as glycogen and starch are synthesized from nucleoside diphosphate sugars, primarily uridine diphosphate glucose (UDPG) and adenosine diphosphate glucose (ADPG). These activated glucose donors act as key intermediates in carbohydrate metabolism and biosynthesis. UDPG primarily involves glycogen synthesis in animals and many bacteria, while ADPG plays a fundamental role in starch synthesis in plants and certain bacteria.UDPG is formed when glucose-1-phosphate reacts with...