Abstract
Cancer-associated fibroblasts (CAFs) play a crucial role in cancer progression and even initiation. However, the origins of CAFs in various cancer types remain controversial, and one of the important hypothesized origins is through epithelial-mesenchymal transition (EMT) from cancer cells. In this study, we investigated whether the HEp-2 laryngeal cancer cells are able to generate CAFs via EMT during tumor formation, which is now still unknown. The laryngeal xenografted tumor model was established by inoculating the HEp-2 laryngeal cancer cell line in nude mice. Primary cultured CAFs from the tumor nodules and matched normal fibroblasts (NFs) from the adjacent connective tissues were subcultured, purified, and verified by immunofluorescence. Migration, invasion, and proliferation potentials were compared between the CAFs and NFs. A co-culture of CAFs with HEp-2 cells and a co-injection of CAFs with HEp-2 cells in nude mice were performed to examine the cancer-promoting potential of CAFs to further verify their identity. Karyotypic analyses of the CAFs, NFs, and HEp-2 cells were conducted. A co-culture of NFs with HEp-2 cells was also performed to examine the expression of activated markers of CAFs. A pathological examination confirmed that the laryngeal xenografted tumor model was successfully established, containing abundant CAFs. Immunocytochemical staining verified the purities and identities of the CAFs and NFs. Although the CAFs manifested higher migration, invasion, proliferation, and cancer-promoting capacities compared with the NFs, an analysis of chromosomes revealed that both the CAFs and NFs showed typical normal mouse karyotypes. In addition, the NFs co-cultured with HEp-2 cells did not show induced expressions of activated markers of CAFs. Our findings reveal that the CAFs in the HEp-2 established laryngeal xenografted tumor are not of laryngeal cancer origin but of mouse origin, indicating that the HEp-2 laryngeal cancer cells cannot generate their own CAFs via EMT in this model.
Highlights
The progression, metastasis, and even initiation of cancer are no longer recognized as independent events that are solely caused by genetic mutations and the uncontrollable growth of malignant cancer cells
cancer-associated fibroblasts (CAFs) in the tumor microenvironment may be derived from various origins, and epithelial-mesenchymal transition (EMT) from cancer cells is considered to be an important origin that accounts for a fraction of the CAFs that are present in tumors [4,5]
We investigated whether widely used laryngeal cancer cells, HEp-2, can generate their own CAFs in the xenografted tumor model via EMT
Summary
The progression, metastasis, and even initiation of cancer are no longer recognized as independent events that are solely caused by genetic mutations and the uncontrollable growth of malignant cancer cells. CAFs found in various cancers exhibit similar perpetually activated phenotypes, neither reverting back to a normal phenotype nor undergoing apoptosis [10]; they demonstrate a high degree of heterogeneity in their origins in different types of cancer [11]. They may be derived from cancer cells or normal epithelial cells through epithelial-mesenchymal transition (EMT), from the activation of resident normal fibroblasts (NFs) via genetic or epigenetic alteration induced by signals from adjacent tumor cells, from endothelial cells through endothelial to mesenchymal transition, or from bone marrow-derived hematopoietic stem cells or mesenchymal stem cells [4,12,13]
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