Hi Angiogenesis In Hnscc

A. Clinical Evidences

The requirement of solid tumors to stimulate an angiogenic response in the host has been shown to be a prerequisite for the development of tumor growth, invasion, and metastasis. Patients with HNSCC frequently are affected with tumor masses of several centimeters in size. Given the fact that only solid tumors as little as 1-2 mm3 in size can grow in an avascular environment, several hypotheses have been raised regarding the capability of HNSCCs to initiate an angiogenic response.

The first experimental indication supporting a correlation between increased angiogenesis and tumor growth derives from the analysis of cutaneous metastasizing melanomas [56,57]. In addition, in 1991, Weidner et al. [58] reported that the density of capillary microvessels was elevated significantly in invasive breast carcinoma, thus being a closer predictor of metastasis than tumor size or grade. Several subsequent experimental studies and clinicopathological reports further confirmed existence of a tumor/blood vessel relationship in various types of solid tumors [46,59,60], such as nonsmall cell lung [61], prostate [62], testicular [63], colorectal, and gastric carcinomas [64], including squamous cell carcinoma of the head and neck.

The first evidence corroborating the induction of blood vessel formation in HNSCC arose from a study conducted by Petruzzelli et al. [65], in which specimens from HNSCC-affected patients were grafted onto the chick chorioallantoic membrane (CAM) of chick embryos. This resulted in a significant augmentation of the angiogenic response in the xenografts compared to normal control tissues (Fig. 7.2).

Median angiogenesis score

FIGURE 7.2 Distribution of control and tumor explant angiogenesis scores. Mann-Whitney rank sum analysis of median angiogenesis scores demonstrated significantly increased neovascularization induced by tumor explants (p- 0.01). Adapted from Petruzzelli et al., Ann. Otol. Rhinol. Laryngol. 102, 215-221 (1993).

Median angiogenesis score

FIGURE 7.2 Distribution of control and tumor explant angiogenesis scores. Mann-Whitney rank sum analysis of median angiogenesis scores demonstrated significantly increased neovascularization induced by tumor explants (p- 0.01). Adapted from Petruzzelli et al., Ann. Otol. Rhinol. Laryngol. 102, 215-221 (1993).

Moreover, the radial outgrowth ("spoke wheel") pattern of CAM vessels was identified in the tumor nodules and was lacking in the nontumor explants.

Is angiogenesis an effective marker in the progression of HNSCC? To date, several controversial observations emerged from various studies attempting to correlate the degree of neovascularization with prognosis, regional occurrence, and metastasis in the squamous cell carcinoma of the head and neck. During the past decades, several reports have been published evaluating the extent of microvessel growth in human neoplastic tissues derived from HNSCC. In general, microvessels are identified by immunohistochemical staining against specific markers for endothelial cells, such as von Willebrand factor, factor VIII, CD31, CD34, CD36, Ulex europaeus I agglutinin, or ABH blood group isoantigens [66-68], Immunoreactive areas are then evalu-ated by determining the intensity of the staining using a 1 to 4+ grading range or by microvessel count per high-power field.

In 1988, Delides et al. [69] by analyzing 25 nasopharyngeal tumors histologically, observed the existence of a correlation between angiogenesis and response to irradiation and survival, thus proposing that tumors with a greater count of microvessels are likely to present a more effective therapeutic response [69]. Analogous findings have been reported in a study conducted by Zatterstrom et al. [70] in which 48 heterogeneous early and late stage HNSCC biopsies were examined by immunostaining with factor VIII monoclonal antiobodies. The significance of the tumor neovascularization in relation of clinical outcome in response to radiotherapy was confirmed (Table 7.1). Nonetheless, contradictory findings were reported in another study in which tumors from 42

TABLE 7.1 Response to Radiotherapy in Relation to Microvessel Density Score above versus below 4.75a
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