HIF-1alpha Expression Profile in Intratumoral and Peritumoral Inflammatory Cells as a Prognostic Marker for Squamous Cell Carcinoma of the Oral Cavity

Abstract

The HIF-1 transcriptional complex is responsible for controlling transcription of over 100 genes involved in cell hypoxia response. HIF-1alpha subunit is stabilized in hypoxia conditions, creating the HIF-1 nuclear transcription factor. In inflammatory cells, high HIF-1alpha expression induces lymphocytic immunosuppression, decreasing tumoral antigen recognition, which promotes tumor growth. The present work investigated the relationship between HIF-1alpha expression in lymphocytes populating the intratumoral and peritumoral region of 56 patients with oral cancer. Our data indicates a prognostic value for this expression. High HIF-1alpha expression in peritumoral inflammatory cells is significantly related to worse patient outcome, whereas high expression in the intratumoral lymphoid cells correlates with a better prognosis. A risk profile indicating the chance of disease relapse and death was designed based on HIF-1alpha expression in tumoral inflammatory cells, defining low, intermediate and high risks. This risk profile was able to determine that high HIF-1alpha expression in peritumoral cells correlates with worse prognosis, independently of intratumoral expression. Low HIF-1alpha in tumor margins and high expression in the tumor was considered a low risk profile, showing no cases of disease relapse and disease related death. Intermediate risk was associated with low expression in tumor and tumor margins. Our results suggest that HIF-1alpha expression in tumor and peritumoral inflammatory cells may play an important role as prognostic tumor marker.

Clinico-pathological prognosticators in oral squamous cell carcinoma

“…78 Other studies have revealed that B regulatory cells in tongue SCC; micro-localization of CD68+ tumour–associated macrophages in tumour stroma; systemic inflammation scores including the modified Glasgow Prognostic Score in patients undergoing potentially curative resection for OSCC; expression of Fas ligand in tumour lymphoid cells; tumour-infiltrating neutrophils; expression of HIF-1α in tumour and peri-tumoural inflammatory cells; tumour-infiltrating lymphocytes and T regulatory cells; CD8+/CD4+ cell ratio; may predict clinical outcome and survival of the patients. 79 –88 On the contrary to the above observations, a study by Affonso et al showed that peri-tumoural inflammation has no prognostic implications in OSCC. 89…”

Clinical and prognostic significance of HIF-1α overexpression in oral squamous cell carcinoma: a meta-analysis

“…3 ), which suggested an association between HIF-1α expression and tumor size. In six studies [ 6 , 19 – 21 , 25 , 26 ], patients with stage III/IV OSCC had higher levels of HIF-1α expression as compared to that in patients with stage I/II tumors. The combined OR was significant (OR = 2.29, 95% CI = 1.50–3.49, I 2 = 37.3%, P = 0.158; fixed-effects model) with no significant heterogeneity (Fig.…”

Prognostic impact of reduced tumor-free margin distance on long-term survival in FIGO stage IB/II vulvar squamous cell carcinoma

“…The notion of a ‘more aggressive’ recurrence affecting the <5 mm margin group is supported by our findings, as patients in the <5 mm margin group who developed a recurrence were 7 times more likely to die from VSCC when compared with patients who developed local recurrences in the ≥5 mm margin group. This is perhaps associated to the peri-tumoral stromal inflammation left in situ following the surgical removal of the tumor, which in time may contribute to the malignant progression of the remaining tissue [ 31 ] and to the development of local and metastatic disease [ 32 ].…”