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Mod Pathol. 2016 Aug;29(8):928-38. doi: 10.1038/modpathol.2016.72. Epub 2016 May 6.

Exosomes in colorectal carcinoma formation: ALIX under the magnifying glass.

Author information

1
Molecular Medicine Research Unit, Hungarian Academy of Sciences, Budapest, Hungary.
2
1st Department of Pathology and Experimental Cancer Research, Semmelweis University and MTA-SE Tumor Progression Research Group, Budapest, Hungary.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
4
2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
5
Department of General Surgery and Surgical Oncology, Uzsoki Teaching Hospital, Budapest, Hungary.

Abstract

Exosomes are small membrane vesicles that have important roles in transporting a great variety of bioactive molecules between epithelial compartment and their microenvironment during tumor formation including colorectal adenoma-carcinoma sequence. We tested the mRNA expression of the top 25 exosome-related markers based on ExoCharta database in healthy (n=49), adenoma (n=49) and colorectal carcinoma (n=49) patients using Affymetrix HGU133 Plus2.0 microarrays. Most related genes showed significantly elevated expression including PGK1, PKM, ANXA5, ENO1, HSP90AB1 and MSN during adenoma-carcinoma sequence. Surprisingly, the expression of ALIX (ALG 2-interacting protein X), involved in multivesicular body (MVB) and exosome formation, was significantly reduced in normal vs adenoma (P=5.02 × 10(-13)) and in normal vs colorectal carcinoma comparisons (P=1.51 × 10(-10)). ALIX also showed significant reduction (P<0.05) at the in situ protein level in the epithelial compartment of adenoma (n=35) and colorectal carcinoma (n=37) patients compared with 27 healthy individuals. Furthermore, significantly reduced ALIX protein levels were accompanied by their gradual transition from diffuse cytoplasmic expression to granular signals, which fell into the 0.6-2 μm diameter size range of MVBs. These ALIX-positive particles were seen in the tumor nests, including tumor-stroma border, which suggest their exosome function. MVB-like structures were also detected in tumor microenvironment including α-smooth muscle actin-positive stromal cells, budding off cancer cells in the tumor front as well as in cancer cells entrapped within lymphoid vessels. In conclusion, we determined the top aberrantly expressed exosome-associated markers and revealed the transition of diffuse ALIX protein signals into a MVB-like pattern during adenoma-carcinoma sequence. These tumor-associated particles seen both in the carcinoma and the surrounding microenvironment can potentially mediate epithelial-stromal interactions involved in the regulation of tumor growth, metastatic invasion and therapy response.

PMID:
27150162
DOI:
10.1038/modpathol.2016.72
[Indexed for MEDLINE]
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