Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?

Although still controversial, the presence of mutant p53 in cancer cells may result in more aggressive tumors and correspondingly worse outcomes. The means by which mutant p53 exerts such pro-oncogenic activity are currently under extensive investigation and different models have been proposed. We focus here on a proposed mechanism by which a subset of tumor-derived p53 mutants physically interact with p53 family members, p63 and p73, and negatively regulate their proapoptotic function. Both cell-based assays and knock-in mice expressing mutant forms of p53 support this model. As more than half of human tumors harbor mutant forms of p53 protein, approaches aimed at disrupting the pathological interactions among p53 family members might be of clinical value.     

Is there a role for chemosensitivity tests in head and neck cancer?

Despite many advances in predictive testing of human malignancies, we are far from using it routinely in clinical practice. Investigating the responsiveness of solid tumors to cytostatic drugs is particularly challenging. Nevertheless, for head and neck cancer, chemosensitivity testing is an increasingly attractive option, since chemotherapy has proven to have curative potential in the therapy of head and neck cancer, in particular in combination with radiation. The significant need for predictive methods to identify patients responsive to therapy, first of all in organ preservation programs, which is an alternative to first-line surgery, had recently renewed the discussion on a possible role of chemosensitivity testing in head and neck cancer. In this review, we discuss the current state of chemosensitivity testing in head and neck cancer. Recent methodological developments, in particular elimination of photochemical artifacts and inclusion of stromal cell response studies, may soon augment the value of ex vivo chemosensitivity testing for the management of head and neck cancer.     

Chemokines and squamous cancer of the head and neck: targets for therapeutic intervention?

The biological properties of squamous carcinoma cells are intimately regulated by a multitude of cytokines and growth factors; the most well studied of these include epidermal growth factor receptor agonists and members of the transforming growth factor-beta family. The recent explosion of research in the field of chemokine function as a mediator of tumor progression has led to the possibility that these small, immunomodulatory proteins also play key roles in squamous carcinogenesis and may, therefore, be potential targets for novel therapeutic approaches.     

p63 and p73: teammates or adversaries?

In this issue of Cancer Cell, Kovacic and colleagues have reexamined the role of STAT1 in murine models of leukemogenesis. Their studies shed new light on the complex interplay between cell-autonomous contributions and host responsiveness to cancer and elucidate a previously unknown role of STAT1 in tumor progression.     

Upregulated interleukin‐6 expression contributes to erlotinib resistance in head and neck squamous cell carcinoma

Despite the role of epidermal growth factor receptor (EGFR) signaling in head and neck squamous cell carcinoma (HNSCC) development and progression, clinical trials involving EGFR tyrosine kinase inhibitors (TKIs) have yielded poor results in HNSCC patients. Mechanisms of acquired resistance to the EGFR TKI erlotinib was investigated by developing erlotinib‐resistant HNSCC cell lines and comparing their gene expression profiles with their parental erlotinib‐sensitive HNSCC cell lines using microarray analyses and subsequent pathway and network analyses. Erlotinib‐resistant HNSCC cells displayed a significant upregulation in immune response and inflammatory pathways compared to parental cells. Interleukin‐6 (IL‐6) was one of thirteen genes that was significantly differentially expressed in all erlotinib‐resistant HNSCC cell lines, which was validated using RT‐PCR and ELISA. Blockade of IL‐6 signaling using the IL‐6 receptor antagonist tocilizumab, was able to overcome erlotinib‐resistance in erlotinib‐resistant SQ20B tumors in vivo. Overall, erlotinib‐resistant HNSCC cells display elevated IL‐6 expression levels compared to erlotinib‐sensitive HNSCC cells and blockade of the IL‐6 signaling pathway may be an effective strategy to overcome resistance to erlotinib and possibly other EGFR TKIs for HNSCC therapy.     

Alteration of radiotherapy fractionation and concurrent chemotherapy: a new frontier in head and neck oncology?

Despite recent advances in multimodality management of patients with stage III-IV head and neck squamous cell carcinoma, the prognosis in these patients remains disappointing. In an attempt to improve treatment outcome, several teams recently investigated the role of altered fractionation radiotherapy in conjunction with systemic chemotherapy. The controlled trials that investigated this combined approach indicate that, although the magnitude of its effect was less marked for survival indices than for local-regional control, the addition of chemotherapy to altered fractionation regimens results in a clear improvement for these endpoints compared with hyperfractionated or accelerated regimens alone. The key challenge now is to optimize the synergism of these regimens in order to increase their therapeutic ratio in terms of both local-regional and systemic outcomes. This review is a critical appraisal of the real opportunities offered by the application of treatments aimed at increasing the dose intensity of radiotherapy delivered concurrently with cytotoxic drugs.     

p53 mutations and resistance to chemotherapy: a stab in the back for p73?

p53 gene is a member of a multigene family that includes p53, p63 and p73. The association of p73 and p63 with cell transformation has been elusive as no genetic or epigenetic alteration of these genes has been uncovered yet. Recent work has shown clearly that p73 is an essential component of the signaling pathway that lead to apoptosis after DNA damage induced by cytotoxic agents use in cancer therapy. Furthermore, it has been established that a sub-category of mutant p53 is able to interact with p73 and inhibit its apoptotic activity. Such discovery will be important for a better understanding of the signaling pathway that lead to resistance to chemotherapy.     

HPV DNA and survivin expression in epithelial oral carcinogenesis: a relationship?

HPV has been thought to be involved in the development of several oral diseases, such as premalignant mucosal lesions and oral carcinoma. Survivin is a recently characterized IAP protein, which is abundantly expressed in most solid and haematological malignancies, but undetectable in normal adult tissues. Aim of this study was to investigate survivin expression and HPV presence in oral premalignant lesions and oral carcinoma. 47 samples of oral tissue including 11 squamous cell carcinomas (OSCC), 16 oral leukoplakias (OL) and 20 normal oral mucosa specimens, after investigation of HPV presence by nested PCR (consensus MY/GP primers) and viral genotype identification by direct sequencing were investigated by immunohistochemistry to detect survivin expression. Survivin expression was evident in 4/7 (57.1%) HPV+ and 4/4 (100%) HPV- OSCC, 6/7 (85.7%) HPV+ and 5/9 (55.5%) HPV- OL and in 0/20 (0%) control samples. Data showed high levels of survivin expression in HPV-positive SCCs, even if mean values were lower than HPV-negative ones, which in particular showed survivin expression in 100% of cases. Conversely, survivin expression was greater in HPV+ precancerous lesions than in HPV- ones. Our findings suggest that survivin may be involved in HPV- mediated deregulation during maturation of squamous epithelium through modulation of the apoptotic processes and, conversely, HPV may have a direct or indirect effect on the regulation of the survivin expression level. In particular, the results of this study suggest distinguishing between cancerous and precancerous oral lesions with respect to survivin expression when HPV infection is present. The most unfavourable behaviour is likely to be for the HPV- OSCC.     

Screening for distant metastases in patients with head and neck cancer: is there a role for (18)FDG-PET?

The detection of distant metastases and second primary tumours at the time of initial evaluation changes the prognosis and influences the selection of treatment modality in patients with HNSCC. Until recently chest CT was the single most effective test to screen for distant metastases in HNSCC patients. In this observational cohort study we prospectively compared the yield of whole body (18)FDG-PET and chest CT to detect distant metastases and synchronous primary tumours. The results of whole body (18)FDG-PET and chest CT were analysed in 34 consecutive HNSCC patients with previously established risk factors for the presence of distant metastases. Four patients were diagnosed with distant metastases or second primary tumours: CT as well as (18)FDG-PET identified one patient with lung metastases and another with primary lung cancer. In addition, (18)FDG-PET detected second primary tumours in two patients (hepatocellular carcinoma and abdominal adenocarcinoma). However increased uptake sites at (18)FDG-PET in lung, liver and pelvis in five patients were not confirmed by other imaging modalities. The added value of whole body (18)FDG-PET versus chest CT was to identify unknown malignancy in 6% of the patients. Confirmation of positive (18)FDG-PET findings is feasible and necessary.     

Assessment of p38α in peripheral blood mononuclear cells (PBMC): a potential blood protein marker of head and neck squamous cell carcinoma

Purpose

Solid tumors involve an inflammatory microenvironment portrayed by immune cells playing role in cancer progression via inflammatory p38α mitogen-activated protein kinase (MAPK) molecule that produces pro-inflammatory cytokines-TNFα, IL1β and IL6. This study quantified and compared the expression of p38α in peripheral blood mononuclear cells (PBMCs) of HNSCC patients with the healthy subjects.

Methods

The PBMC were isolated from the 35 control and 83 HNSCC patients. The expression of p38α in PBMCs was assessed using surface plasmon resonance (SPR), ELISA and western blot analysis.

Results

p38α levels were found to be over-expressed in HNSCC patients 0.98 ng/μl (95 % CI 0.95–1.02) as compared to controls 0.46 ng/μl (95 % CI 0.42–0.50) (p < 0.0001).

Conclusion

p38α is over-expressed in PBMCs of HNSCC patients and may play a role in the progression of cancer. This research may translate a protein marker for HNSCC to clinical oncologist for therapeutic intervention and use as a predictive marker.