S100A4 is a Biomarker of Tumorigenesis, EMT, Invasion, and Colonization of Host Organs in Experimental Malignant Mesothelioma

Our plain-English summary of S100A4 is a Biomarker of Tumorigenesis, EMT, Invasion, and Colonization of Host Organs in Experimental Malignant Mesothelioma, by J.S. Nader, J. Guillon, C. Petit, et al (Cancers, 2020).

The study

• Authors: J.S. Nader, J. Guillon, C. Petit, A. Boissard, F. Franconi, S. Blandin, S. Lambot, M. Grégoire, V. Verrièle, B. Nawrocki-Raby, P. Birembaut, O. Coqueret, C. Guette, D.L. Pouliquen
• Journal: Cancers
• Published: 2020;12(4)
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Recent findings suggest that S100A4, a protein involved in communication between stromal cells and cancer cells, could be more involved than previously expected in cancer invasiveness. To investigate its cumulative value in the multistep process of the pathogenesis of malignant mesothelioma (MM), SWATH-MS (sequential window acquisition of all theoretical fragmentation spectra), an advanced and robust technique of quantitative proteomics, was used to analyze a collection of 26 preneoplastic and neoplastic rat mesothelial cell lines and models of MM with increasing invasiveness. Secondly, proteomic and histological analyses were conducted on formalin-fixed paraffin-embedded sections of liver metastases vs. primary tumor, and spleen from tumor-bearing rats vs. controls in the most invasive MM model. We found that S100A4, along with 12 other biomarkers, differentiated neoplastic from preneoplastic mesothelial cell lines, and invasive vs. non-invasive tumor cells in vitro, and MM tumors in vivo. Additionally, S100A4 was the only protein differentiating preneoplastic mesothelial cell lines with sarcomatoid vs. epithelioid morphology in relation to EMT (epithelial-to-mesenchymal transition). Finally, S100A4 was the most significantly increased biomarker in liver metastases vs. primary tumor, and in the spleen colonized by MM cells. Overall, we showed that S100A4 was the only protein that showed increased abundance in all situations, highlighting its crucial role in all stages of MM pathogenesis.

In plain English

This was a laboratory study in rats that measured proteins with a technique called SWATH-MS. The cells came from 33 F344 rats injected into the abdomen with 10 mg of crocidolite fibers at 8 weeks of age. The authors analyzed 22 preneoplastic (pre-cancerous) and 4 neoplastic (cancerous) rat mesothelial cell lines and tumors grown from the cancerous lines in rats. They also examined liver metastases, spleens from 10 tumor-bearing and 10 control rats, and, in a preliminary test, two human mesothelioma samples. Of 1661 proteins detected in each cell line, 13 changed in the same direction across all four comparisons. S100A4 was the only one to rise continuously and significantly. Among the candidate proteins, it was also the only one that distinguished pre-cancerous lines with sarcomatoid versus epithelioid shape. It was among the most significant changes between later and earlier liver metastases. It showed the most significant increase in spleens of tumor-bearing rats. The authors concluded that S100A4 was the only protein increased in all situations studied.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal and laboratory experiment: protein analysis (SWATH-MS proteomics) and tissue examination of rat mesothelial cell lines and rat mesothelioma tumor models, with a preliminary test on two human tumor samples
• Who was studied: 22 preneoplastic and 4 neoplastic rat mesothelial cell lines from a collection established in 2011 from 33 F344 rats. Tumors were grown from the 4 neoplastic lines in genetically matched rats. Organs from 20 rats bearing the most invasive tumor (M5-T1) were examined. Spleens from 10 M5-T1 tumor-bearing rats and 10 control rats were analyzed. Two human mesothelioma tumor pieces came from the Reims University Hospital tumor bank. Work was done in France.
• Exposure: Rats received a single injection into the abdominal cavity (intraperitoneal) of 10 mg crocidolite fibers (UICC analytical sample) at 8 weeks of age. Cell lines were derived 136 to 415 days later.
• Main results:
  • In the rat cell lines, 595 proteins differed between neoplastic and both groups of preneoplastic lines. Of these, 90 also differed between the three invasive and the one non-invasive neoplastic cell line.
  • Of those 90 proteins, S100A4 was the single protein that also distinguished preneoplastic rat cell lines with sarcomatoid morphology from those with epithelioid morphology. It was higher in the sarcomatoid lines.
  • Across all four comparisons (neoplastic vs. each preneoplastic group, invasive vs. non-invasive cell lines, invasive vs. non-invasive rat tumors), 13 proteins changed in the same direction. Among them, S100A4 alone showed a continuous and significant increase from preneoplastic to neoplastic cells and from non-invasive to invasive cells and tumors.
  • In rats with the most invasive model (M5-T1), liver metastases at the final stage were compared with those at the advanced stage; 148 proteins differed. S100A4 and two glycolysis enzymes (TPIS and PGAM1) showed the most significant ratios.
  • Spleens from 10 M5-T1 tumor-bearing rats were compared with spleens from 10 control rats. Eight candidate proteins changed significantly, and S100A4 showed the most significant increase. Among other S100 proteins detected in spleen, only S100A9 increased.
  • In a preliminary comparison of two human mesothelioma tumor pieces (sarcomatoid vs. epithelioid), S100A4 was significantly increased in both the tumor and its periphery.
• The authors' conclusion: The authors concluded that S100A4 was the only protein whose abundance increased in all situations studied. In their view, this highlights a crucial role for it in the multistep process of experimental mesothelioma development, including tumor formation, EMT, invasion, and colonization of host organs.
• Limitations the authors state:
  • The authors described the human analysis as a preliminary investigation on only two tumor samples.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Carcinogenesis, Mesothelioma, Mesothelial Cells, Sarcomatoid, Epithelioid.

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