On approaches to the functional restoration of salivary glands damaged by radiation therapy for head and neck cancer, with a review of related aspects of salivary gland morphology and development

Abstract

Radiation therapy for cancer of the head and neck can devastate the salivary glands and partially devitalize the mandible and maxilla. As a result, saliva production is drastically reduced and its quality adversely altered. Without diligent home and professional care, the teeth are subject to rapid destruction by caries, necessitating extractions with attendant high risk of necrosis of the supporting bone. Innovative techniques in delivery of radiation therapy and administration of drugs that selectively protect normal tissues can reduce significantly the radiation effects on salivary glands. Nonetheless, many patients still suffer severe oral dryness. I review here the functional morphology and development of salivary glands as these relate to approaches to preventing and restoring radiation-induced loss of salivary function. The acinar cells are responsible for most of the fluid and organic material in saliva, while the larger ducts influence the inorganic content. A central theme of this review is the extent to which the several types of epithelial cells in salivary glands may be pluripotential and the circumstances that may influence their ability to replace cells that have been lost or functionally inactivated due to the effects of radiation. The evidence suggests that the highly differentiated cells of the acini and large ducts of mature glands can replace themselves except when the respective pools of available cells are greatly diminished via apoptosis or necrosis owing to severely stressful events. Under the latter circumstances, relatively undifferentiated cells in the intercalated ducts proliferate and redifferentiate as may be required to replenish the depleted pools. It is likely that some, if not many, acinar cells may de-differentiate into intercalated duct-like cells and thus add to the pool of progenitor cells in such situations. If the stress is heavy doses of radiation, however, the result is not only the death of acinar cells, but also a marked decline in functional differentiation and proliferative capacity of all of the surviving cells, including those with progenitor capability. Restoration of gland function, therefore, seems to require increasing the secretory capacity of the surviving cells, or replacing the acinar cells and their progenitors either in the existing gland remnants or with artificial glands.

Three dimensional image analysis of minor salivary glands in 180-day rats born with macrosomia

“…The formation and acinar differentiation of the mixed secretion salivary glands occur mainly prenatally [25,26], and the intra-uterine forming epigenetic changes in metabolism and the morphofunctional state of the glands can persist for life and affect the cariogenic situation in oral cavity.…”

Growth Factors Polymerized Within Fibrin Hydrogel Promote Amylase Production in Parotid Cells

“…38,39 Dedifferentiation (as indicated by decreased amylase expression and cell polarity) is the biggest challenge that must be overcome for the creation of a functional artificial salivary gland. 40 GFR-MG contains six growth factors, four of which have been demonstrated to induce no increase in the amylase promoter activity (i.e., bFGF at 0.1 ng/mL, PDGF at < 5 ng/ mL, NGF at < 0.2 ng/mL, and TGFb at 1.7 ng/mL). 31,34 Of the two remaining growth factors, one (EGF at < 0.5 ng/mL) was shown to increase the acinar cell-specific amylase promoter activity.…”

Histamine prevents functional and morphological alterations of submandibular glands induced by ionising radiation

“…It is well known that ionising radiation induces damage to the major salivary glands, resulting in severe alterations in their structure and function (Burlage et al 2001, 2008, Nagler 2002, Vissink et al 2003, Lombaert et al 2008, Redman 2008, Avila et al 2009). …”

“…After irradiation, damage to the oral mucosa and particularly severe morphological and functional alterations of the salivary glands occur resulting in salivary dysfunction (Valdez et al 1993, Burlage et al 2001, 2008, Nagler 2002. Xerostomia is the main clinical effect, a common, disturbing side-effect among patients treated with high doses of ionising radiation that leads to considerable morbidity (Valdez et al 1993, Nagler 2002, Vissink et al 2003, Dirix et al 2006.…”

“…Regeneration originates from putative stem cells residing in the ductal compartment from which complete recovery is induced within a week after ductal obstruction. Irreversible hyposalivation after irradiation-induced damage is caused not only by the death of acinar cells, but also by a marked decline in functional differentiation and proliferative capacity of all of the surviving cells, mainly by sterilisation of these primitive glandular stem cells with progenitor capability, which prevents replenishment of aged saliva producing cells, thus altering tissue homeostasis (O'Connell et al 1999, Takahashi et al 2004, Lombaert et al 2008, Redman 2008. Although new radiation techniques enabled significant sparing, the amount of normal salivary gland tissue irradiated may still be substantial and results in clinically relevant and irreversible radiation-induced xerostomia.…”