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The S100A7/8/9 Proteins: Novel Biomarker and Therapeutic Targets for Solid Tumor Stroma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sanjay Mishra, Dinesh Ahirwar, Mohd W. Nasser, Ramesh K. Ganju
It was also found that the antibody-based neutralization of RAGE showed decreased metastasis in an established model of lung metastasis. Here, we have found that the binding of S100A7 to RAGE activated the ERK-NF-κB signaling and causes increased cell migration. To study the effects of S100A7 in-vivo, we have also developed a transgenic breast cancer mouse model of mS100a7a15 and it was observed that the treatment of either soluble RAGE or RAGE neutralizing antibody significantly reduced the breast tumor progression and subsequent metastasis [53]. Recently, several neutralizing antibodies of S100A7 have been generated and studies have shown that blocking S100A7-RAGE axis is essential for inhibiting metastasis in preclinical mouse models. In this study, authors have identified the potential role of S100A7 in the formation of a proinflammatory and proangiogenic tumor microenvironment which supports the tumor progression and metastasis. Moreover, they have also observed the important contribution of S100A7 in the formation of the pre-metastatic niche which favors the metastasis to distant organs. Overall, majority of the preclinical data presented in the literature strongly suggest that S100A7 plays crucial role in enhancing TNBC growth and metastasis via modulating tumor microenvironment and serve as novel biomarker for early detection as well as novel target for therapy (Fig. 1).
Early response evaluation of PD-1 blockade in NSCLC patients through FDG-PET-CT and T cell profiling of tumor-draining lymph nodes
Published in OncoImmunology, 2023
Frank J. Borm, Jasper Smit, Joyce Bakker, Maurits Wondergem, Egbert F. Smit, Adrianus J. de Langen, Tanja D. de Gruijl
Another source of potential predictive biomarkers is the tumor-draining lymph node (TDLN). TDLNs are heavily influenced by the tumor, which is illustrated by the observation that TDLNs become immunosuppressive within a week after tumor implantation.4 This pre-metastatic niche is induced by the tumor through immune modulatory exosomes and soluble mediators. Suppression of dendritic cells, a low CD4/CD8 ratio, and high rates of Tregs have all been related to metastatic spread to TDLNs.5 Moreover, recent preclinical studies have provided proof that the TDLN is essential for the induction of an effective antitumor response upon the initiation of immune checkpoint inhibitor (ICI) therapy.5 Its unique immunological properties and its essential role in ICI treatment response make the TDLN a logical site for early response biomarker discovery.
The cellular and molecular mediators of metastasis to the lung
Published in Growth Factors, 2022
Oliver Cucanic, Rae H. Farnsworth, Steven A. Stacker
Interestingly, primary tumour cells may have the ability to prime the secondary site of metastasis for tumour colonisation before their arrival. In 1889, Stephen Paget was among the first who proposed this cross-talk between primary or circulating tumour cells and the microenvironment in secondary sites of metastasis (Liu and Cao 2016; Langley and Fidler 2011; Paget 1889). This elegant botanical analogy deemed the “seed and soil” hypothesis provided valuable insight to our understanding of tumour metastasis and the phenomenon known as organotropism in metastasis, where tumour cells (the “seed”) have higher proclivities to specific organ sites (the “soil”) where there is a favourable microenvironment for metastasis. In the decades hence, other researchers have elucidated the cellular components and corresponding molecular mechanisms underlying organotropic metastasis. Furthermore, there is emerging evidence that tumours may begin to condition distant “soils” to promote tumour cell colonisation prior to the arrival of tumour cells at the site. This formation of a supportive and favourable microenvironment in secondary organs is now termed the pre-metastatic niche (PMN) and represents how we understand the biochemistry and cellular biology of metastatic microenvironments and their development (Liu and Cao 2016; Langley and Fidler 2011).
Identification of novel, immune-mediating extracellular vesicles in human lymphatic effluent draining primary cutaneous melanoma
Published in OncoImmunology, 2019
Rachel L.G. Maus, James W. Jakub, Tina J. Hieken, Wendy K. Nevala, Trace A. Christensen, Shari L. Sutor, Thomas J. Flotte, Svetomir N. Markovic
In an effort to identify candidate L-EV cargo capable of mediating this observed effect, 18 proteins with defined roles in immune modulation were found to be present in all L-EV preparations (Figure 2(d)), including S100A9, a myeloid chemoattractant previously shown to inhibit DC maturation.31 Recently characterized as a damage-associated molecular pattern molecule (DAMP), S100A9 has demonstrated pro-inflammatory properties in both epithelial cells of the skin and the myeloid cell lineage.35 In tumor-bearing mice, S100A9 has been shown to promote accumulation of myeloid-derived suppressor cells and inhibit DC differentiation.31 The mechanistic model that is emerging suggests systemic factors including VEGF-A, TGFβ and TNFα are secreted from the primary tumor microenvironment and induce expression of myeloid chemoattractants S100A8 and S100A9 in future metastatic sites.36 Upregulation of these chemokines in pre-metastatic sites has resulted in the recruitment of immature myeloid cells to the lung in B16 melanoma mouse models to date.16,37 In this way, an immune-compromised, pre-metastatic niche is initiated by circulating cytokine and chemokines, promoting future metastatic habitats.