Anti-S100A4 Antibody Therapy Is Efficient in Treating Aggressive Prostate Cancer and Reversing Immunosuppression: Serum and BiopsyS100A4as a Clinical Predictor

Abstract

◥S100A4 oncoprotein plays a critical role during prostate cancer progression and induces immunosuppression in host tissues. We hypothesized that S100A4-regulated oncogenic activity in immunosuppressed prostate tumors promotes growth of neoplastic cells, which are likely to become aggressive. In the current study, we investigated whether biopsy-S100A4 gene alteration independently predicts the outcome of disease in patients and circulatory-S100A4 is druggable target for treating immunosuppressive prostate cancer. Aided by DECIPHER-genomic test, we show biopsy-S100A4 overexpression as predictive of (i) poor ADT response and (ii) high risk of mortality in 228 radical prostatectomy-treated patients. Furthermore, analysis of tumor genome data of more than 1,000 patients with prostate cancer (PRAD/SU2C/FHCRC studies) validated the association of S100A4-alteration to poor survival and metastasis. We show that increased serum-S100A4 levels are associated to the prostate cancer progression in patients. The prerequisite for metastasis is the escape of tumor cells via vascular system. We show that extracellular-S100A4 protein as a growth factor induces vascular transmigration of prostate cancer cells and bone demineralization thus forms an ideal target for therapies for treating prostate cancer. By employing surface plasmon resonance and isothermal titration calorimetry, we show that mab6B12 antibody interacts with and neutralizes S100A4 protein. When tested for therapeutic efficacy, the mab6B12 therapy reduced the (i) osteoblastic demineralization of bone-derived MSCs, (ii) S100A4target (NFkB/MMP9/VEGF) levels in prostate cancer cells, and (iii) tumor growth in a TRAMPC2 syngeneic mouse model. The immuno-profile analysis showed that mAb6B12-therapyT cells; and (iii) decreased levels of IL5/6/12/13, sTNFR1, and serum-RANTES. We suggest that S100A4-antibody therapy has clinical applicability in treating immunosuppressive prostate cancer in patients.

The novel transcriptomic signature of angiogenesis predicts clinical outcome, tumor microenvironment and treatment response for prostate adenocarcinoma

“…Then, we identified a total of 23 ARGs that significantly correlated with PCa patients' survival. In concordance with previous studies which investigate the ARG solely in prostate cancer, genes including NRP1 (Tse et al 2017), JAG2 (Kwon et al 2016), COL5A2 (Ren et al 2021), POSTN (Cattrini et al 2018), FSTL1 (Zhao et al 2019), PF4 (Baselga et al 2008), JAG1 (Terada et al 2014), COL3A1 (Angel et al 2020), VCAN (Asano et al 2017), VEGFA (Zhan et al 2013), SPP1 (Pang et al 2019), VTN (Niu et al 2016), and S100A4 (Ganaie et al 2020) were identified as unfavorable prognosis-related biomarkers in prostate cancer. Meanwhile, the prognosis roles of APP (Takayama et al 2009) and FGFR1 (Yang et al 2013b) were controversial with previous studies, which needed further validation and study.…”

Follow-Up Biomarkers in the Evolution of Prostate Cancer, Levels of S100A4 as a Detector in Plasma

“…In PC, the role of S100A4-antibody therapy and its clinical applicability in treating immunosuppressive PC patients has previously been suggested [25]. Its role in promot- Although all markers are statistically significant (see Table 1) S100A4 is the biomarker with the best performance, with an AUC value of 0.735 (95% CI = 0.668-0.803) and a specificity of 90.32%.…”

“…Fluids biomarkers currently in use for diagnosis, prognosis, and relapse-monitoring of localized PC remain centered around PSA, with new strategies for genomic biomarkers still presenting a challenge [24]. At present, the established prognostic factors (ISUP, stage, and PSA) are insufficient to separate PC patients with high risk of cancer progression; moreover, molecular markers for metastatic propensity remain elusive [25]. RNA biomarkers are experiencing an increased interest in predicting progression-free survival and OS [26].…”

“…In PC, the role of S100A4-antibody therapy and its clinical applicability in treating immunosuppressive PC patients has previously been suggested [25]. Its role in promoting cell proliferation and epithelial-mesenchymal transition characteristics in tumor cells, inducing regulating bone metastasis, has also been proposed [12].…”

S100A4 in the Physiology and Pathology of the Central and Peripheral Nervous System

“…Moreover, S100A4 is considered a metastasis-promoting factor also because the protein Moreover, S100A4 is considered a metastasis-promoting factor also because the protein is released by activated stromal cells (e.g., fibroblasts, immune and vascular cells) in the tumor microenvironment, where it fosters growth factors release, angiogenesis and overall tumor survival. The increased protein secretion associated with tumor development and invasiveness has made S100A4 a good biomarker for different metastatic cancers, where it also assumes a prognostic value, since its increase is associated with poor patients survival [12][13][14][15][16]. Besides these roles, S100A4 controls different cellular pathways, exerting in this way numerous effects on processes that are cell-and tissue-type dependent.…”