Elsevier

Oral Oncology

Volume 51, Issue 7, July 2015, Pages 643-651
Oral Oncology

Review
Cancer stem cells and field cancerization of Oral squamous cell carcinoma

https://doi.org/10.1016/j.oraloncology.2015.04.006Get rights and content

Highlights

  • Field cancerization refers to transformed cells in the tumor-adjacent fields.

  • Stem cells in this field, are possible candidates for amassing transforming mutations.

  • Tumorigenic/migratory cancer stem cells can effect mono-/polyclonal FC models.

  • Molecular evidence for association of FC with CSC-specific markers.

  • CSCs proposed to be tools of FC; CSC markers may be predictive of disease relapse in OSCC.

Summary

Oral squamous cell carcinoma (OSCC) has a high propensity for local failure, which is attributed to recurrence at the primary site or the development of second primary tumors (SPT). Field cancerization that refers to the existence of transformed cells in areas adjacent to the primary tumor, has been attributed to be one of the probable reasons underlying disease relapse. The carcinogenic process necessitates multiple molecular events for the transformation of a normal cell into a cancer cell. This implies that only the long-time residents of the epithelium, such as the stem cells, might be the candidates capable of accumulating these genetic hits. These transformed stem cells- the ‘Cancer stem cells’ (CSCs), are further known to be equipped with the properties of tumor initiation and migration, both of which are essential for orchestrating field cancerization. The concept that the CSCs might be responsible for field cancerization in OSCC has not been explored extensively. If the role of CSCs as the primary units of field cancerization process is established, their presence in the mucosa adjacent to the tumor may be an indicator for local recurrence and/or development of second primary tumors. In this review, we examine the available evidence in literature exploring the possibilities of CSCs driving the process of field cancerization and thereby being the underlying mechanism for disease recurrence and development of SPT.

Introduction

Loco-regional recurrence and development of second primary tumors are the major factors impacting the survival rate in head and neck cancer. Despite intense, multi-modal local therapy, recurrence at the primary sites occurs in about 10–30% of the patients while the incidence rate of second primary tumor varies between 2% and 30% [1], [2], [3]. ‘Field cancerization,’ referred to as the occurrence of molecular abnormalities in the tumor adjacent mucosal field, is a concept that attempts to explain local disease failure, both recurrence and occurrence of second primary tumors. In epithelial cancers, tumor adjacent normal mucosa is also exposed to the carcinogen and is reported to develop abnormal molecular changes. The major molecular alterations, considered as the hallmarks of field cancerization, are mutations in oncogenes/tumor suppressor genes, loss of heterozygosity (LOH) and genomic instability. The cells with these alterations are known to gain the capacity to develop and expand the neoplastic field. These mutant, pre-cancerous cells are then hypothesized to replace the normal cells in the mucosa, consequently rendering the epithelia susceptible to further genetic/epigenetic hits, thereby triggering tumor formation [1], [4].

Cancer stem cells (CSC) are a pluripotent sub-population of cells in the tumor that have properties of self-renewal, tumor initiation, migration and metastasis [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], whether these cells can orchestrate the process of field cancerization is a question that has not been addressed in detail. In this review, we have assessed the available evidences towards the role of CSCs in the process of field cancerization and thereby the potential of CSC-specific biomarkers as a predictor of local recurrence and second primary tumor formation.

Section snippets

Principle

The concept of ‘Field cancerization’, coined by Slaughter in 1953, proposes that the normal tissue adjacent to the tumor harbor certain pre-neoplastic genetic finger prints which can eventually lead to development of local recurrence or second primary tumors. Slaughter and his group based this concept on the following observations: (i) tumor adjacent mucosa being molecularly ‘abnormal’ (ii) multifocal areas of precancerous changes develop due to a prolonged and widespread exposure to

Cancer stem cells

Cancer stem cells (CSCs) are a small population of cells within the tumor that are tissue specific, slow dividing and with unlimited self-renewal capacity [21]. The origin of these cells is explained by three different processes. The first model envisaged that a normal, tissue-specific stem cell undergoes several genetic as well as epigenetic alterations to give rise to a CSC [4]. This model gains significance owing to the fact that normal and cancer stem cells share attributes such as

Cancer stem cells in field cancerization-a possible model

On the basis of the above evidences we have proposed a model of field cancerization orchestrated by the CSCs.

The continuous exposure of the oral mucosa to carcinogens results in molecular alterations that ultimately lead to the induction of cancer stem cell-like behavior in a stepwise manner. The cancer stem cells originate either by transformation of the normal stem cells (NSCs) or by de-differentiation of the tumor cells and migrate through normal mucosa to develop the field. In view of the

Diagnostic and therapeutic implication of CSC in field cancerization

Patients treated for OSCC have about 3–7% per year risk for development of second primary tumors [SPT] [101], [102], [103]. It may develop either as synchronous tumors that develop simultaneously or within six months of diagnosis of the index tumor, or as metachronous tumors that develop six months after the index tumor [16]. The patients with SPT have very high mortality rate [101], [102], [103] and these lesions should be differentiated from recurrent tumors as the biology, treatment response

Conclusion

The concept of field cancerization implies a cause-effect relationship with the generation of second primary and recurrent tumors. Literature points out to the fact that this process may be CSC-driven. Establishment and experimental validation of this concept will provide new insights into the mechanism of loco-regional recurrence and development of SPTs. Identification of CSC-specific molecules that drive the filed cancerization process may be used for prognosis and provide novel targets for

Conflict of interest

None declared

Acknowledgement

This work is funded in part by Mazumdar Shaw Center for Translation Research, Mazumdar Shaw Medical Foundation, Narayana Hrudayalaya Foundation and Department of Science and Technology (DST), Government of India. SM is funded with Women-Scientist A award (ID: SR/WOS-A/LS-224/2012), DST, Government of India.

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