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Functional Characterization of Oral Cancer Initiating Cells

Epithelial Cell Regulation and Transformation Program
Integrative Biology and Infectious Diseases Branch
Division of Extramural Research


To build a knowledge base for developing new targeted and effective therapies for Oral Squamous Cell Carcinomas (OSCCs) by elucidating the cellular and molecular properties of oral Cancer-Initiating Cells (CICs) and the composition and architecture of oral CIC niches.  The intent is to move the field beyond the phenotypic characterization of CICs and to encourage studies that would provide actionable molecular data to target CICs effectively for the treatment of OSCC.


OSCCs represent the majority of head and neck cancers with ~45,000 new cases diagnosed each year in the U.S. alone.  The 5-year survival rate of OSCC patients is only ~50% and this number has not improved significantly during the past few decades. The major reasons attributed to this poor survival rate are late diagnosis, disease recurrence, distant metastasis and resistance to therapy.  Despite advances in our understanding of the etiology and progression of oral cancer at the molecular level, current therapeutic options for patients are limited, involving primarily surgical and cytotoxic approaches, which are inefficient, cause substantial morbidity and compromise the quality of life for the patient. The discovery of ClCs (also referred to as cancer stem cells) in different types of tumors has fueled renewed hopes for early diagnosis and the development of a new generation of effective therapies that rely on increased understanding of the developmental hierarchy and functions of cell types within a tumor.  The CIC hypothesis posits that the ability of cancer to evade traditional therapies is largely driven by a subpopulation of cells with stem-like characteristics, such as the ability to self-renew and give rise to more tumor cells.  A corollary from this hypothesis is that therapies specifically targeting CICs within a tumor mass should provide a superior treatment option to that of conventional therapies, and could potentially cure the disease by eliminating the “root” of the cancer. Moreover, elucidation of specific OSCC CIC signature could open up unprecedented opportunities for developing highly sensitive molecular probes for enabling early disease diagnosis and treatment optimization.

While intriguing, the CIC hypothesis has been met with controversy, with some critics arguing that at least some of the data in favor of the functional significance of CICs in cancer initiation and progression might have resulted from artifacts of in vitro CIC manipulation and from deficiencies of immunocompromised in vivo models commonly used for testing CICs function. Recently, however, three independent studies across three different types of solid tumors - skin, intestine and brain - provided strong evidence in support of a functional role for CICs in endogenous tumor development in vivo, lending additional credence to the validity of this line of research for advancing novel cancer treatment.

Gaps and Opportunities

While recent studies have provided preliminary evidence for the existence of oral CICs, the majority of CIC work to date has involved their phenotypic characterization at the cellular level and proof of concept studies to demonstrate putative roles in oral cancer initiation and persistence.  Considerable knowledge gaps remain in our understanding of oral cancer CIC biology and function, including their cellular origin; their role in endogenous tumor development and progression in vivo; nature of OSCC-specific CIC markers; nature of ligands and signaling pathways that control their self-renewal, proliferation, differentiation, and survival; composition and architecture of their niches; and modes of interaction between the niches and CICs.  Advancing our understanding of the cellular properties and function of oral CICs will be vital for the design and development of a new generation of targeted and effective therapies that would improve survival rates of patients with OSCC and possibly would cure the disease. Obtaining answers to the following questions will drive the field further: 

1.    Can we identify oral CIC-specific cell surface markers that are not expressed in normal cells to allow identification, characterization and separation of oral CICs within the bulk of the tumor?

2.    Is there a minimal genetic or epigenetic signature that distinguishes oral CICs from other cancer cells that form the bulk of OSCC, and from normal cells?

3.    Can we adapt and/or develop reliable and robust in vitro and in vivo functional assays for testing cancer initiating capacity of oral CICs?

4.    Can we genetically trace the lineage of oral CICs in their native in vivo environment of primary tumors to provide direct evidence for their functional role in tumor initiation and progression?

5.    Can we delineate the differentiation dynamics and phenotypic fluidity of oral CICs that could in turn be exploited for therapeutic strategies?

6.    Can we identify and target signaling pathway(s) specific for oral CICs without affecting the normal cells?

7.    Can we identify, track and target a single circulating oral CIC with metastatic potential from OSCC?



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This page last updated: February 26, 2014