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Title: Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches

Abstract

The research on oral cancer has focused mainly on the cancer cells, their genetic changes and consequent phenotypic modifications. However, it is increasingly clear that the tumor microenvironment (TME) has been shown to be in a dynamic state of inter-relations with the cancer cells. The TME contains a variety of components including the non-cancerous cells (i.e., immune cells, resident fibroblasts and angiogenic vascular cells) and the ECM milieu [including fibers (mainly collagen and fibronectin) and soluble factors (i.e., enzymes, growth factors, cytokines and chemokines)]. Thus, it is currently assumed that TME is considered a part of the cancerous tissue and the functionality of its key components constitutes the setting on which the hallmarks of the cancer cells can evolve. Therefore, in terms of controlling a malignancy, one should control the growth, invasion and spread of the cancer cells through modifications in the TME components. This mini review focuses on the TME as a diagnostic approach and reports the recent insights into the role of different TME key components [such as carcinoma-associated fibroblasts (CAFs) and inflammation (CAI) cells, angiogenesis, stromal matrix molecules and proteases] in the molecular biology of oral carcinoma. Furthermore, the impact of TME components on clinical outcomes andmore » the concomitant need for development of new therapeutic approaches will be discussed. - Highlights: • Tumor depth and budding, hypoxia and TME cells associate with worse prognosis. • Pro-tumoral CAFs and CAI cells aid proliferation, invasion and spread hypoxia. • Some ECM-bound factors exert pro-angiogenic or pro-tumor activities. • Tumor spread is greatly dependent on ECM proteolysis, mediated by TME cells. • Direct targeting of TME components for treatment is still experimental.« less

Authors:
 [1];  [2];  [2];  [3];  [4];  [5];  [6];  [1];  [7];  [4];  [7]
  1. Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, and Medical Research Center, Oulu (Finland)
  2. (Finland)
  3. Institute of Pathology, The Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan (Israel)
  4. (Israel)
  5. Department of Oral Medicine and Diagnostic Sciences, King Saud University, Riyadh (Saudi Arabia)
  6. Oulu University Central Hospital, Oulu (Finland)
  7. Department of Oral Pathology and Oral Medicine, School of Dentistry, Tel Aviv University, Tel Aviv 69978 (Israel)
Publication Date:
OSTI Identifier:
22416909
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 325; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARCINOMAS; FIBROBLASTS; INFLAMMATION; LYMPHOKINES; MACROPHAGES; NATURAL KILLER CELLS; ORAL CAVITY; RECEPTORS; STEM CELLS

Citation Formats

Salo, Tuula, E-mail: Tuula.salo@oulu.fi, Oulu University Central Hospital, Oulu, Institute of Dentistry, University of Helsinki, Helsinki, Vered, Marilena, Department of Oral Pathology and Oral Medicine, School of Dentistry, Tel Aviv University, Tel Aviv 69978, Bello, Ibrahim O., Nyberg, Pia, Bitu, Carolina Cavalcante, Zlotogorski Hurvitz, Ayelet, Department of Oral and Maxillofacial Surgery, Rabin Medical Center, Beilinson Campus, Petah Tikva, and Dayan, Dan. Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches. United States: N. p., 2014. Web. doi:10.1016/J.YEXCR.2013.12.029.
Salo, Tuula, E-mail: Tuula.salo@oulu.fi, Oulu University Central Hospital, Oulu, Institute of Dentistry, University of Helsinki, Helsinki, Vered, Marilena, Department of Oral Pathology and Oral Medicine, School of Dentistry, Tel Aviv University, Tel Aviv 69978, Bello, Ibrahim O., Nyberg, Pia, Bitu, Carolina Cavalcante, Zlotogorski Hurvitz, Ayelet, Department of Oral and Maxillofacial Surgery, Rabin Medical Center, Beilinson Campus, Petah Tikva, & Dayan, Dan. Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches. United States. doi:10.1016/J.YEXCR.2013.12.029.
Salo, Tuula, E-mail: Tuula.salo@oulu.fi, Oulu University Central Hospital, Oulu, Institute of Dentistry, University of Helsinki, Helsinki, Vered, Marilena, Department of Oral Pathology and Oral Medicine, School of Dentistry, Tel Aviv University, Tel Aviv 69978, Bello, Ibrahim O., Nyberg, Pia, Bitu, Carolina Cavalcante, Zlotogorski Hurvitz, Ayelet, Department of Oral and Maxillofacial Surgery, Rabin Medical Center, Beilinson Campus, Petah Tikva, and Dayan, Dan. Tue . "Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches". United States. doi:10.1016/J.YEXCR.2013.12.029.
@article{osti_22416909,
title = {Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches},
author = {Salo, Tuula, E-mail: Tuula.salo@oulu.fi and Oulu University Central Hospital, Oulu and Institute of Dentistry, University of Helsinki, Helsinki and Vered, Marilena and Department of Oral Pathology and Oral Medicine, School of Dentistry, Tel Aviv University, Tel Aviv 69978 and Bello, Ibrahim O. and Nyberg, Pia and Bitu, Carolina Cavalcante and Zlotogorski Hurvitz, Ayelet and Department of Oral and Maxillofacial Surgery, Rabin Medical Center, Beilinson Campus, Petah Tikva and Dayan, Dan},
abstractNote = {The research on oral cancer has focused mainly on the cancer cells, their genetic changes and consequent phenotypic modifications. However, it is increasingly clear that the tumor microenvironment (TME) has been shown to be in a dynamic state of inter-relations with the cancer cells. The TME contains a variety of components including the non-cancerous cells (i.e., immune cells, resident fibroblasts and angiogenic vascular cells) and the ECM milieu [including fibers (mainly collagen and fibronectin) and soluble factors (i.e., enzymes, growth factors, cytokines and chemokines)]. Thus, it is currently assumed that TME is considered a part of the cancerous tissue and the functionality of its key components constitutes the setting on which the hallmarks of the cancer cells can evolve. Therefore, in terms of controlling a malignancy, one should control the growth, invasion and spread of the cancer cells through modifications in the TME components. This mini review focuses on the TME as a diagnostic approach and reports the recent insights into the role of different TME key components [such as carcinoma-associated fibroblasts (CAFs) and inflammation (CAI) cells, angiogenesis, stromal matrix molecules and proteases] in the molecular biology of oral carcinoma. Furthermore, the impact of TME components on clinical outcomes and the concomitant need for development of new therapeutic approaches will be discussed. - Highlights: • Tumor depth and budding, hypoxia and TME cells associate with worse prognosis. • Pro-tumoral CAFs and CAI cells aid proliferation, invasion and spread hypoxia. • Some ECM-bound factors exert pro-angiogenic or pro-tumor activities. • Tumor spread is greatly dependent on ECM proteolysis, mediated by TME cells. • Direct targeting of TME components for treatment is still experimental.},
doi = {10.1016/J.YEXCR.2013.12.029},
journal = {Experimental Cell Research},
number = 2,
volume = 325,
place = {United States},
year = {Tue Jul 15 00:00:00 EDT 2014},
month = {Tue Jul 15 00:00:00 EDT 2014}
}
  • The turnover of extracellular matrix liberates various cryptic molecules with novel biological activities. Endostatin is an endogenous angiogenesis inhibitor that is derived from the non-collagenous domain of collagen XVIII. Although there are a large number of studies on its anti-tumor effects, the molecular mechanisms are not yet completely understood, and the reasons why endostatin has not been successful in clinical trials are unclear. Research has mostly focused on its anti-angiogenic effect in tumors. Here, we aimed to elucidate how endostatin affects the behavior of aggressive tongue HSC-3 carcinoma cells that were transfected to overproduce endostatin. Endostatin inhibited the invasion ofmore » HSC-3 cells in a 3D collagen–fibroblast model. However, it had no effect on invasion in a human myoma organotypic model, which lacks vital fibroblasts. Recombinant endostatin was able to reduce the Transwell migration of normal fibroblasts, but had no effect on carcinoma associated fibroblasts. Surprisingly, endostatin increased the proliferation and decreased the apoptosis of cancer cells in organotypic models. Also subcutaneous tumors overproducing endostatin grew bigger, but showed less local invasion in nude mice xenografts. We conclude that endostatin affects directly to HSC-3 cells increasing their proliferation, but its net effect on cancer invasion seem to depend on the cellular composition and interactions of tumor microenvironment. - Highlights: • Endostatin affects not only angiogenesis, but also carcinoma cells and fibroblasts. • Endostatin increased carcinoma cell proliferation, but decreased 3D invasion. • The invasion inhibitory effect was sensitive to the microenvironment composition. • Fibroblasts may be a factor regulating the fluctuating roles of endostatin.« less
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