Solid tumors consist of the tumor parenchyma and stroma. The standard concept of oncology is that the tumor parenchyma regulates the tumor stroma and promotes tumor progression, and that the tumor parenchyma represents the tumor itself and defines the biological characteristics of the tumor tissue. Thus, the tumor stroma plays a pivotal role in assisting tumor parenchymal growth and invasiveness and is regarded as a supporter of the tumor parenchyma. The tumor parenchyma and stroma interact with each other. However, the influence of the stroma on the parenchyma is not clear. Therefore, in this study, we investigated the effect of the stroma on the parenchyma in oral squamous cell carcinoma (OSCC). We isolated tumor stroma from two types of OSCCs with different invasiveness (endophytic type OSCC (ED-st) and exophytic type OSCC (EX-st)) and examined the effect of the stroma on the parenchyma in terms of proliferation, invasion, and morphology by co-culturing and co-transplanting the OSCC cell line (HSC-2) with the two types of stroma. Both types of stroma were partially positive for alpha-smooth muscle actin. The tumor stroma increased the proliferation and invasion of tumor cells and altered the morphology of tumor cells in vitro and in vivo. ED-st exerted a greater effect on the tumor parenchyma in proliferation and invasion than EX-st. Morphological analysis showed that ED-st changed the morphology of HSC-2 cells to the invasive type of OSCC, and EX-st altered the morphology of HSC-2 cells to verrucous OSCC. This study suggests that the tumor stroma influences the biological characteristics of the parenchyma and that the origin of the stroma is strongly associated with the biological characteristics of the tumor.
The stromal cells in the tumor microenvironment (TME) can influence the progression of multiple types of cancer; however, data on oral squamous cell carcinoma (OSCC) are limited. In the present study, the effects of verrucous squamous cell carcinoma-associated stromal cells (VSCC-SCs), squamous cell carcinoma-associated stromal cells (SCC-SCs) and human dermal fibroblasts (HDFs) on the tumor nest formation, proliferation, invasion and migration of HSC-3 cells were examined in vitro using Giemsa staining, MTS, and Transwell (invasion and migration) assays, respectively. The results revealed that both the VSCC-SCs and SCC-SCs inhibited the tumor nest formation, and promoted the proliferation, invasion and migration of OSCC cells in vitro . Furthermore, the effects of VSCC-SCs, SCC-SCs and HDFs on the differentiation, proliferation, invasion and migration of OSCC cells in vivo were evaluated by hematoxylin and eosin staining, tartrate-resistant acid phosphatase staining, immunohistochemistry and double-fluorescent immunohistochemical staining, respectively. The results demonstrated that the VSCC-SCs promoted the differentiation, proliferation, invasion and migration of OSCC cells, while the SCC-SCs inhibited the differentiation, and promoted the proliferation, invasion and migration of OSCC cells in vivo . Finally, microarray data were used to predict genes in VSCC-SCs and SCC-SCs that may influence the progression of OSCC, and those with potential to influence the differential effects of VSCC-SCs and SCC-SCs on the differentiation of OSCC. It was found that C-X-C motif chemokine ligand (CXCL)8, mitogen-activated protein kinase 3 (MAPK3), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), C-X-C motif chemokine ligand 1 (CXCL1) and C-C motif chemokine ligand 2 (CCL2) may be involved in the crosstalk between VSCC-SCs, SCC-SCs and OSCC cells, which regulates the progression of OSCC. Intercellular adhesion molecule 1 (ICAM1), interleukin (IL)1B, Fos proto-oncogene, AP-1 transcription factor subunit (FOS), bone morphogenetic protein 4 (BMP4), insulin (INS) and nerve growth factor (NGF) may be responsible for the differential effects of VSCC-SCs and SCC-SCs on the differentiation of OSCC. On the whole, the present study demonstrates that both VSCC-SCs and SCC-SCs may promote the progression of OSCC, and SCC-SCs were found to exert a more prominent promoting effect; this may represent a potential regulatory mechanism for the progression of OSCC.
Stromal cells in the tumor microenvironment (TME) can regulate the progression of numerous types of cancer; however, the bone invasion of oral squamous cell carcinoma (OSCC) has been poorly investigated. In the present study, the effect of verrucous SCC-associated stromal cells (VSCC-SCs), SCC-associated stromal cells (SCC-SCs) and human dermal fibroblasts on bone resorption and the activation of HSC-3 osteoclasts in vivo were examined by hematoxylin and eosin, AE1/3 (pan-cytokeratin) and tartrate-resistant acid phosphatase staining. In addition, the expression levels of matrix metalloproteinase (MMP)9, membrane-type 1 MMP (MT1-MMP), Snail, receptor activator of NF-κB ligand (RANKL) and parathyroid hormone-related peptide (PTHrP) in the bone invasion regions of HSC-3 cells were examined by immunohistochemistry. The results suggested that both SCC-SCs and VSCC-SCs promoted bone resorption, the activation of osteoclasts, and the expression levels of MMP9, MT1-MMP, Snail, RANKL and PTHrP. However, SCC-SCs had a more prominent effect compared with VSCC-SCs. Finally, microarray data were used to predict potential genes underlying the differential effects of VSCC-SCs and SCC-SCs on bone invasion in OSCC. The results revealed that IL1B, ICAM1, FOS, CXCL12, INS and NGF may underlie these differential effects. In conclusion, both VSCC-SCs and SCC-SCs may promote bone invasion in OSCC by enhancing the expression levels of RANKL in cancer and stromal cells mediated by PTHrP; however, SCC-SCs had a more prominent effect. These findings may represent a potential regulatory mechanism underlying the bone invasion of OSCC.
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