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

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.

Friend or Foe: S100 Proteins in Cancer

“…The evaluated expression of S100 proteins could also be detected in malignant mesothelioma [203]. In this context, S100A4 was shown to be a promising biomarker, as it correlated with tumour progression, morphologic changes related to EMT, invasion, and metastasis [204]. However, more research is needed to validate the role of S100 family members in malignant mesothelioma.…”

Cross-Species Proteomics Identifies CAPG and SBP1 as Crucial Invasiveness Biomarkers in Rat and Human Malignant Mesothelioma

“…Firstly, the decrease observed between PNep and PNint was concomitant with the first dramatic decrease in the expression of Cdh1 and Il10 , and parallel increase in the expression of Acta 2 , Tgfb1 [ 15 ]. Secondly, the new decrease observed between PNsarc1 and PNsarc2, and continuous decrease from PNep to PNsarc2, confirm the existence of links to both the level of expression of Hifa [ 18 ] and EMT process [ 15 ]. Thirdly, the decrease observed between preneoplastic cell lines with both epithelioid and sarcomatoid morphologies and neoplastic cell lines leads to the conclusion that SBP1 presents additional interest as a biomarker of neoplastic transformation.…”

“…We next investigated whether some of the 28 candidate biomarkers (the 18 increased and 7 decreased proteins listed in the 3 versus 1 comparison, plus CAPG, FABP4, and LAMB2) common to the rat and human MM ( Figure 2 D) exhibited additional abundance changes during the carcinogenesis process. For that purpose, we first examined the SWATH-MS proteomic data of the whole biocollection of rat mesothelial cell lines, looking in particular at the list of 674 proteins differentiating preneoplastic cell lines with sarcomatoid versus epithelioid morphology [ 18 ]. In a second step, we compared this list to another list of 192 proteins discriminating the two subgroups of preneoplastic cell lines with sarcomatoid morphology PNsarc2 vs. PNsarc1, which differ in their relative expression of Hif1a [ 18 ].…”

“…For that purpose, we first examined the SWATH-MS proteomic data of the whole biocollection of rat mesothelial cell lines, looking in particular at the list of 674 proteins differentiating preneoplastic cell lines with sarcomatoid versus epithelioid morphology [ 18 ]. In a second step, we compared this list to another list of 192 proteins discriminating the two subgroups of preneoplastic cell lines with sarcomatoid morphology PNsarc2 vs. PNsarc1, which differ in their relative expression of Hif1a [ 18 ]. Finally, comparing the 94 proteins exhibiting significant abundance changes in the two previous situations with the 28 candidate biomarkers described above (see Figure 2 D and Section 2.2 and Section 2.3 ), led to six proteins common to the four proteomic analyzes ( Figure 6 A).…”

“…Both CAPG and RAB31 shared a similar pattern of changes during the course of rat mesothelial cell carcinogenesis. However, these changes were only observed in the first two subgroups of preneoplastic cell lines with sarcomatoid morphology, suggesting a link to increased Hifa expression [ 18 ]. The pattern of changes observed for SBP1 markedly contrasted with these situations as decreases in abundance were observed at three main stages of the carcinogenic process.…”