Oral cancer stem cells - properties and consequences

Abstract Research on cancer stem cells (CSCs) has greatly increased in the field of medicine and pathology; however, some conceptual misunderstandings are still present among the public as well as within the general scientific community that is not yet familiar with the subject. The very first problem is the misinterpretation of CSCs as a synonym of their normal counterparts, the well-known stem cells (SCs). Particularly in Dentistry, another common mistake is the misinterpretation of oral CSCs as normal tooth-derived SCs. The present review aims to clarify important concepts related to normal SCs and CSCs, as well as discuss the relevance of CSCs to the development, metastasis and therapy resistance of oral squamous cell carcinoma.


Introduction
For several years the concept of "stem cells" has important prospect of being able to create new human tissues in the laboratory and use them to replace those lost by injury or disease. Such stem cell concepts applied to Dentistry, as well as to general Medicine, could be greatly enhanced by researches exploring the ability of stem cells to generate new tissues such as mucosa and bone tissues and, eventually, regenerate dental tissues including perhaps even the whole teeth.
Recently, however, the dental literature has begun to contain references to "cancer stem cells" (CSCs) and these have quite a different concept. These are the cells that have the ability to stimulate the growth of oral cancers and enable tumours to resist therapy. This review will describe how CSCs differ from normal stem cells, how they can be isolated and studied, how they have special properties and, of most importance, how they are responsible for the spreading of cancer and how they might be targeted for destruction. There is now good evidence that CSCs exist in most tumours but this review will focus mainly on oral squamous cell carcinoma, which comprises the great majority of malignant oral cancers.

Background of oral cancer
Oral squamous cell carcinoma (OSCC) is the most commonly occurring oral malignancy and one of the most widely occurring cancers throughout the world 9,25,33 . OSCC is a malignancy that arises in the squamous epithelium lining the oral cavity and includes tumours found on the tongue, lip, gingival, 13,25 .  32 ; however, the main negative prognostic factor is the presence of lymph node metastasis, which occurs in 25 to 65% of cases 15,29 .
The treatment for early-stage OSCC is generally single modality, either surgery or radiotherapy. In cases of locally advanced OSCC, the treatment is multimodal, with either surgery followed by adjuvant radiation or chemo-radiation, as indicated by 27 .
Approximately half of all patients survive 5 years after stage of the disease at diagnosis 35  They are therefore described as "totipotent" and, unusually for stem cells, they are transient. As the embryonic development proceeds, these totipotent stem cells become directed towards differentiation into the many distinct tissue types of the adult individual (e.g. stem cells for blood, bones, mucosa, etc.). As they do so they lose some of their developmental potential and become either "pluripotent", that is, restricted to forming only a few types of tissues, or "unipotent",  Oral cancer stem cells As stem cells are ultimately responsible for all the normal tissue growth and renewal occurring in the body, it therefore logically follows that stem cells are also likely to be responsible for cancer growth.
However, although the idea that CSCs stimulate the The isolation of CSCs from oral cancers has mainly been performed with the CD44 marker that was initially used to isolate breast cancer CSCs. CD44 is an adhesion molecule that binds itself to hyaluronan and its expression is necessary for the maintenance of the CSC's properties. CSCs lose their "stemness" when CD44 is experimentally reduced 44 . However, a problem with CD44, and also with all other CSC Cancer stem cells and treatment failure As they are the cells stimulating tumour growth, elimination of CSCs is necessary for the elimination of tumours. However, many studies have now shown that CSCs are more resistant than other tumour cells to chemotherapy and radiotherapy 7 . In vitro assays show that when CD44-high CSCs are irradiated or exposed to chemotherapy, they may be over 10 times more resistant to apoptosis than CD44-low cells 18 .
The sensitivity of surrounding normal tissues to high doses of chemo-and radio-therapies restricts the dose levels that can be administered and, despite the various methods of targeting, the dose provided may the CSCs. Clinically, therefore, the tumour may appear to shrink, and even perhaps disappear, only for a few remaining CSCs to begin to divide and subsequently regenerate it. Local tumour recurrence is a major problem for OSCC therapy and elimination of CSCs is a target of therapy but one that is made more complex by the heterogeneity of CSCs as discussed below.
Epithelial to mesenchymal transition Aknowledgments