Cellular changes in the tumor microenvironment of human esophageal squamous cell carcinomas
- 283 Downloads
The growth, invasiveness, and metastasis of human cancers are not only determined by the cancer cells but also by their microenvironment. The purpose of this study was to extend our previous studies and to examine the cellular changes in tumor microenvironment (stroma) of esophageal squamous cell carcinomas (ESCCs). The proliferative activity, cellular components, and angiogenesis status in different compartments (non-tumor stroma, tumor stroma, and tumor periphery stroma) of ESCCs were evaluated by immunohistochemistry. The results revealed a hyperproliferative rate labeled by Ki-67 in stromal cells in tumor area as compared with that in stromal cells in non-tumor area, which resulted in the increased densities of myofibroblasts (labeled by smooth muscle actin (SMA)-alpha), lymphocytes (labeled by CD3), macrophages (labeled by CD68), and the activation of angiogenesis characterized by increased microvessel density (MVD) and the increased expression of the proangiogenic factors (vascular endothelial growth factor and interleukin 8) in the tumor stroma. Further analysis showed that the changes of stromal cell density were more significant in the area of periphery tumor stroma than that of stroma between tumor nests. Most cellular changes were significantly associated with lymph node involvement. Double immunohistochemistries with PCNA/CD3, PCNA/CD68, and PCNA/SMA-alpha revealed that these cells present in the ESCC tumor stroma had a proliferative capacity. The cells present in the tumor microenvironment of ESCCs were greatly activated, suggesting that microenvironmental components may be involved in the cancer growth and progression.
KeywordsStroma Carcinoma Esophagus
Proliferating cell nuclear antigen
Indoleamine 2, 3-dioxygenase
Esophageal squamous cell carcinoma
We express our sincere gratitude to Ms. Dana Frederick, Department of Cell Biology, University of Massachusetts Medical School for manuscript proofreading.
Conflicts of interest
- 5.Gholamin M, Moaven O, Memar B, Farshchian M, Naseh H, Malekzadeh R, Sotoudeh M, Rajabi-Mashhadi MT, Forghani MN, Farrokhi F, Abbaszadegan MR. Overexpression and interactions of interleukin-10, transforming growth factor beta, and vascular endothelial growth factor in esophageal squamous cell carcinoma. World J Surg. 2009;33:1439–45.PubMedCrossRefGoogle Scholar
- 13.Yu L, Wu WK, Li ZJ, Li HT, Wu YC, Cho CH. Prostaglandin E(2) promotes cell proliferation via protein kinase C/extracellular signal regulated kinase pathway-dependent induction of c-Myc expression in human esophageal squamous cell carcinoma cells. Int J Cancer. 2009;125:2540–6.PubMedCrossRefGoogle Scholar
- 15.Moussai D, Mitsui H, Pettersen JS, Pierson KC, Shah KR, Suarez-Farinas M, Cardinale IR, Bluth MJ, Krueger JG, Carucci JA. The human cutaneous squamous cell carcinoma microenvironment is characterized by increased lymphatic density and enhanced expression of macrophage-derived VEGF-C. J Investig Dermatol. 2011;131:229–36.PubMedCrossRefGoogle Scholar
- 16.Thode C, Jorgensen TG, Dabelsteen E, Mackenzie I, Dabelsteen S. Significance of myofibroblasts in oral squamous cell carcinoma. J Oral Pathol Med: Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2011;40:201–7.CrossRefGoogle Scholar
- 19.Zips D, Eicheler W, Bruchner K, Jackisch T, Geyer P, Petersen C, van der Kogel AJ, Baumann M. Impact of the tumour bed effect on microenvironment, radiobiological hypoxia and the outcome of fractionated radiotherapy of human FaDu squamous-cell carcinoma growing in the nude mouse. Int J Radiat Biol. 2001;77:1185–93.PubMedCrossRefGoogle Scholar
- 41.Krzystek-Korpacka M, Matusiewicz M, Diakowska D, Grabowski K, Blachut K, Konieczny D, Kustrzeba-Wojcicka I, Terlecki G, Banas T. Elevation of circulating interleukin-8 is related to lymph node and distant metastases in esophageal squamous cell carcinomas—implication for clinical evaluation of cancer patient. Cytokine. 2008;41:232–9.PubMedCrossRefGoogle Scholar