In humans, the S100 protein family is composed of 21 members that exhibit a high degree of structural similarity, but are not functionally interchangeable. This family of proteins modulates cellular responses by functioning both as intracellular Ca(2+) sensors and as extracellular factors. Dysregulated expression of multiple members of the S100 family is a common feature of human cancers, with each type of cancer showing a unique S100 protein profile or signature. Emerging in vivo evidence indicates that the biology of most S100 proteins is complex and multifactorial, and that these proteins actively contribute to tumorigenic processes such as cell proliferation, metastasis, angiogenesis and immune evasion. Drug discovery efforts have identified leads for inhibiting several S100 family members, and two of the identified inhibitors have progressed to clinical trials in patients with cancer. This Review highlights new findings regarding the role of S100 family members in cancer diagnosis and treatment, the contribution of S100 signalling to tumour biology, and the discovery and development of S100 inhibitors for treating cancer.

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S100 proteins in cancer

Human papillomaviruses (HPV) are associated with nearly all cervical cancers, 20% to 30% of head and neck cancers (HNC), and other cancers. Because HNCs also arise in HPV-negative patients, this type of cancer provides unique opportunities to define similarities and differences of HPV-positive versus HPV-negative cancers arising in the same tissue. Here, we describe genome-wide expression profiling of 84 HNCs, cervical cancers, and site-matched normal epithelial samples in which we used laser capture microdissection to enrich samples for tumor-derived versus normal epithelial cells. This analysis revealed that HPV+ HNCs and cervical cancers differed in their patterns of gene expression yet shared many changes compared with HPV− HNCs. Some of these shared changes were predicted, but many others were not. Notably, HPV+ HNCs and cervical cancers were found to be up-regulated in their expression of a distinct and larger subset of cell cycle genes than that observed in HPV− HNC. Moreover, HPV+ cancers overexpressed testis-specific genes that are normally expressed only in meiotic cells. Many, although not all, of the hallmark differences between HPV+ HNC and HPV− HNC were a direct consequence of HPV and in particular the viral E6 and E7 oncogenes. This included a novel association of HPV oncogenes with testis-specific gene expression. These findings in primary human tumors provide novel biomarkers for early detection of HPV+ and HPV− cancers, and emphasize the potential value of targeting E6 and E7 function, alone or combined with radiation and/or traditional chemotherapy, in the treatment of HPV+ cancers. [Cancer Res 2007;67(10):4605–19]

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Fundamental differences in cell cycle deregulation in human papillomavirus-positive and human papillomavirus-negative head/neck and cervical cancers.

Activation of nuclear factor (NF)-κB, one of the most investigated transcription factors, has been found to control multiple cellular processes in cancer including inflammation, transformation, proliferation, angiogenesis, invasion, metastasis, chemoresistance and radioresistance. NF-κB is constitutively active in most tumor cells, and its suppression inhibits the growth of tumor cells, leading to the concept of 'NF-κB addiction' in cancer cells. Why NF-κB is constitutively and persistently active in cancer cells is not fully understood, but multiple mechanisms have been delineated including agents that activate NF-κB (such as viruses, viral proteins, bacteria and cytokines), signaling intermediates (such as mutant receptors, overexpression of kinases, mutant oncoproteins, degradation of IκBα, histone deacetylase, overexpression of transglutaminase and iNOS) and cross talk between NF-κB and other transcription factors (such as STAT3, HIF-1α, AP1, SP, p53, PPARγ, β-catenin, AR, GR and ER). As NF-κB is 'pre-active' in cancer cells through unrelated mechanisms, classic inhibitors of NF-κB (for example, bortezomib) are unlikely to mediate their anticancer effects through suppression of NF-κB. This review discusses multiple mechanisms of NF-κB activation and their regulation by multitargeted agents in contrast to monotargeted agents, thus 'one size does not fit all' cancers.

NF-κB addiction and its role in cancer: ‘one size does not fit all’

Dysregulated molecular networks in head and neck carcinogenesis

Optimal treatment for recurrent/metastatic head and neck cancer

Head and neck squamous-cell carcinoma (HNSCC) is the sixth most common cancer worldwide and, disappointingly, survival rates are not improving. Moreover, HNSCC has a severe impact on the quality of life of patients and survivors, and the significant morbidity subsequent to treatment often mandates long-term multidisciplinary care, which places significant financial pressures on the treating institution. Therefore, prevention and early diagnosis of high-risk pre-malignant lesions are high priorities for reducing deaths due to head and neck cancer. Recent advances have begun to elucidate the different aetiologies of HNSCCs in relation to previous pre-malignancies and to identify which pre-malignant lesions are likely to progress to malignancy.

Profiling early head and neck cancer.

217 Immortality is one of the recognised hallmarks of cancer. Head and neck cancers (HNSCCs) may be preceded by recognisable premalignancies, such as leukoplakias and erythroplakias, which have widely different progression rates. However, by current histopathology methods, it is impossible to predict prognosis of dysplasias in individual patients. To investigate the molecular changes associated with HNSCC progression, we have isolated cultures from biopsies of 20 HNSCCs and 20 dysplasias, as well as normal oral mucosa, using the feeder layer method of Rheinwald and colleagues. Although the majority of head and neck cancers (HNSCC) are immortal, a subset has a mortal phenotype in vivo (1-3) and generally these have a better prognosis. A minority of dysplasias are also immortal and this is consistently associated with specific molecular changes, for example loss of p16INK4A and retinoic acid receptor-beta expression, p53 mutations and activation of telomerase (4-6). Thus acquisition of immortality and invasiveness can be acquired independently. By gene expression profiling of HNSCC cultures followed by validation in biopsies by IHC, we have demonstrated that mortal HNSCCs express markers commonly associated with motility and invasion, as well as chemokines, whereas immortal HNSCCs have a greater tendency to recur and show elevated expression of cell cycle markers and loss of differentiation characteristics (recently reviewed in (7)). We have also identified an immortality gene expression signature common to immortal HNSCCs and dysplasias, some of which are p53-target genes. It also appears possible to identify gene expression patterns characteristic of cultured high risk dysplasias that may be precursors to the mortal and immortal HNSCC types. This could potentially be valuable diagnostically, if confirmed in larger in vivo prospective studies. 1. J. E. Burnset al., Br J Cancer 67, 1274 (1993). 2. K. G. Edington, O. P. Loughran, I. J. Berry, E. K. Parkinson, Mol Carcinog 13, 254 (1995). 3. K. E. Gordonet al., Cancer Res 63, 458 ( 2003). 4. F. McGregoret al., Cancer Res 57, 3886 (1997). 5. F. McGregoret al., Cancer Res 62, 4757 ( 2002). 6. A. Muntoniet al., Oncogene 22, 7804 ( 2003). 7. K. D. Hunter, E. K. Parkinson, P. R. Harrison, Nature Reviews Cancer , in press (February 2005).

Paul R. Harrison

Papers

Profiling early head and neck cancer.

Pathways of progression of head and neck carcinomas and premalignancies revealed by gene expression profiling.