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Stromal SPOCK1 supports invasive pancreatic cancer growth
- Source :
- Molecular Oncology, Molecular oncology, 11(8), 1050-1064. Elsevier
- Publication Year :
- 2017
- Publisher :
- Wiley, 2017.
-
Abstract
- Pancreatic ductal adenocarcinoma (PDAC) is marked by an abundant stromal deposition. This stroma is suspected to harbor both tumor‐promoting and tumor‐suppressing properties. This is underscored by the disappointing results of stroma targeting in clinical studies. Given the complexity of tumor–stroma interaction in PDAC, there is a need to identify the stromal proteins that are predominantly tumor‐promoting. One possible candidate is SPOCK1 that we previously identified in a screening effort in PDAC. We extensively mined PDAC gene expression datasets, and used species‐specific transcript analysis in mixed‐species models for PDAC to study the patterns and driver mechanisms of SPOCK1 expression in PDAC. Advanced organotypic coculture models with primary patient‐derived tumor cells were used to further characterize the function of this protein. We found SPOCK1 expression to be predominantly stromal. Expression of SPOCK1 was associated with poor disease outcome. Coculture and ligand stimulation experiments revealed that SPOCK1 is expressed in response to tumor cell‐derived transforming growth factor‐beta. Functional assessment in cocultures demonstrated that SPOCK1 strongly affects the composition of the extracellular collagen matrix and by doing so, enables invasive tumor cell growth in PDAC. By defining the expression pattern and functional properties of SPOCK1 in pancreatic cancer, we have identified a stromal mediator of extracellular matrix remodeling that indirectly affects the aggressive behavior of PDAC cells. The recognition that stromal proteins actively contribute to the protumorigenic remodeling of the tumor microenvironment should aid the design of future clinical studies to target specific stromal targets.
- Subjects :
- 0301 basic medicine
transforming growth factor‐beta
Cancer Research
Pathology
medicine.medical_specialty
Stromal cell
endocrine system diseases
extracellular matrix
SPOCK1
pancreatic ductal adenocarcinoma
Extracellular matrix
Mice
03 medical and health sciences
0302 clinical medicine
tumor cell invasion
Stroma
Cell Line, Tumor
Pancreatic cancer
Gene expression
stroma
Genetics
medicine
Extracellular
Animals
Humans
Neoplasm Invasiveness
Research Articles
Tumor microenvironment
biology
General Medicine
Transforming growth factor beta
medicine.disease
digestive system diseases
Neoplasm Proteins
Pancreatic Neoplasms
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
biology.protein
Cancer research
Molecular Medicine
Proteoglycans
Carcinoma, Pancreatic Ductal
Research Article
Subjects
Details
- ISSN :
- 15747891 and 18780261
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Molecular Oncology
- Accession number :
- edsair.doi.dedup.....46b5d0df68e5a485873a18ad847c8d3d