Human papillomaviruses as therapeutic targets in human cancer

Abstract

Cervical carcinomas are almost universally associated with high-risk human papillomavirus (HPV) infections, and are a leading cause of cancer death in women worldwide. HPV oncoproteins contribute to cancer initiation and progression and their expression is necessary for the maintenance of the transformed state. The fact that the initiating oncogenic insult, infection with a high-risk HPV and viral oncoprotein expression, is common to almost all cervical cancers offers unique opportunities for prevention, early detection, and therapy. The potential for prevention has been realized by introduction of prophylactic vaccines that are to prevent transmission of specific high-risk HPVs. Given, however, that these vaccines have no therapeutic efficacy and HPV-associated cervical cancers arise years if not decades after the initial infection, it has been estimated that there will be no measurable decline of HPV-associated tumors before 2040. Cervical cancer alone will be diagnosed in more than 375,000 US women between now and 2040. Other HPV-associated anogenital and head and neck cancers are predicted to afflict another 700,000 men and women over this time period. Hence, therapeutic efforts to combat high-risk HPV-associated disease remain of critical importance.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Human papillomavirus (HPV) genome organization. (A) The HPV16 genome is shown as a black circle; arrows indicate the early (E; black) and late (L; red) promoters in the long control region (LCR). Early (E) and late (L) open reading frames (blue) are expressed at different stages during epithelial differentiation. (B) Schematic representation of the minimal HPV sequences integrated into a host chromosome. Integration is a frequent event during malignant progression of high-risk HPV-associated lesions. Expression of the HPV E6 and E7 oncoproteins from the viral LCR is universally maintained in HPV-associated cervical cancers, whereas other portions of the viral genomes, including the E5 oncoprotein, are generally no longer expressed after integration. (C) Schematic representation of the HPV16 E5 (top), E6 (middle), and E7 (bottom) oncoproteins. Sequences involved in targeting known cellular proteins that are relevant for cellular transformation are indicated as red boxes (C, cysteine; L, leucine; Y, tyrosine; E, glutamic acid; X, any amino acid). The cysteine-rich sequence in E5 (CXXC) aids in formation of homodimers. The cysteine-rich domains (CXXC-X29-CXXC) in E6 and E7 are evolutionarily related and function as zinc-binding domains. The amino terminal domain of the E7 oncoprotein that shares sequence similarity to the adenovirus early 1A protein (Ad E1A) and simian vacuolating virus 40 large tumor antigen (SV40 TAg), which contains the binding site for the retinoblastoma tumor suppressor protein (pRB), is also shown. See Introduction and Oncogenic Activities of High-Risk HPVs for details. TM, transmembrane domain.

Fig 2.

Human papillomavirus (HPV) infection of epithelial cells. HPVs infect basal cells of squamous epithelia through sites of mechanical trauma. Infections with high-risk HPVs can lead to dysplasia and carcinoma in situ and to invasive squamous cell carcinoma. Progression is a rare and slow process and many lesions regress spontaneously. Dysplasia is characterized by expansion of basal-like cells into the suprabasal layer and mitotic activity in these layers. Multipolar mitoses can occur as a consequence of E7 oncoprotein expression and contribute to genomic instability. Malignant progression is frequently accompanied by integration of portions of the HPV genome into a host cell chromosome. This leads to increased HPV E6/E7 oncoprotein expression, loss of E5 expression, and failure to produce viral progeny. See Epidemiology and Natural History of HPV Infections for details.

Fig 3.

Transforming activities of high-risk human papillomavirus (HPV) oncoproteins. Major mechanisms utilized by the high-risk HPV E5, E6, and E7 oncoproteins to induce specific hallmarks of cellular transformation. See Oncogenic Activities of High-Risk HPVs for details.