Perhaps the most famous wart in British history

sat on the face of Oliver Cromwell, the Lord Protector of England during the period of the Commonwealth (1653– 58). When commissioning a portrait of himself,

he told the painter, Sir Peter Lely: ‘I desire you would use all your skill to paint my picture truly like me, and not flatter me at all; but remark all the roughness, pimples, warts and everything, otherwise I will never pay a farthing for it.’ Nor was any attempt made to disguise the blemish on his statue, which stands proudly outside the House of Commons.

More than 100 different types of HPV exist, of which most are benign. About 30 types are spread by sexual contact and are classified as either low or high risk. Some types of HPV cause genital warts, single or multiple bumps that appear in the genital areas of men and women including the vagina, cervix, vulva, penis, and rectum. Many of those infected with HPV have no symptoms. Other types cause common skin warts, such as those found on the hands and soles of the feet (source: NAID/ NIH, USA).

Table 17.3  Protein inhibiitors of activated STATs

Oncogenes, malignancy, and signal transduction

Viral oncogenes

Infection by viruses carrying oncogenes can cause malignant cell growth. Although first recognized as causative agents in avian cancers just over 100 years ago (page 298), for much of the 20th century there was doubt that any human cancers were initiated in this way. Even now, almost all the information in this area refers to non-human animals. There are a number of problems here. First of all, as was already apparent in the first decade of the century,52-54 demonstration of a viral mode of transmission depends on the induction

of disease by transfer of tissue filtrates from animal to animal. Some viruses only become oncogenic as a consequence of multiple passages and through different animal species. Secondly, while there are many human cancers that are certainly associated with viral infection, in most cases it is far from certain whether it is the virus that actually initiates the condition or whether it is merely permissive of induction by another agent, such as a chemical carcinogen.

An exception is the human papilloma virus (HPV), the causative agent of skin warts55 and epithelial (cervical) cancer. In general, the transforming products of the viral oncogenes behave as persistently activated mutants of (hijacked) endogenous cellular proteins having key regulatory roles in mitogenesis.

Figure 17.12 is an illustration of how the avian Rous sarcoma oncogene v-Src product (RSVH1) has arisen from a change of the amino acid composition of the C-terminus of Src. Most significantly, this involves the loss of the most C-terminal tyrosine residue with the result that the mutated protein, v-Src is

unable to fold into its inactive state. Alternatively, viral oncogene products are authentic viral proteins that interfere with the functioning of nuclear proteins such as the tumour suppressors p53 and Rb. Examples are the transforming

Fig 17.12  From c-Src to the deregulated kinase v-Src.

(a) c-Src exists in two states. In its inactive form its SH2 domain folds back and binds to pY530 in the C-terminal segment. Dephosphorylation of pY530 or displacement by a higher affinity phosphotyrosine releases the SH2 domain, allowing Src to adopt its open form and become phosphorylated in its activation segment (Y419). (b) Ribbon diagram of c-Src in its inactive and active states. (c) v-Src lacks C-terminal residues that include Y530. It cannot adopt the closed conformation and is constitutively active.57 (2src58, 1y5759).

antigens (T-antigens) of DNA papovaviruses such as simian vacuolating virus SV-40 (primate), BK (human), or JC (human).56,67

Non-viral oncogenes

Tumours that are not caused by viral infection (such as those caused by chemical carcinogens or radiation, or simply due to the multiple errors that accumulate as a consequence of ageing) also express persistently activated gene products. As an example of the role of oncogenes in cell transformation, mutated forms of Ras are found in 40% of all human

cancers60 and in more than 90% of pancreatic carcinomas. These oncogenes are gain-of-function mutants of the wild-type proteins. They include receptor tyrosine kinases, adaptor proteins, and guanine nucleotide exchange factors. Serine and threonine protein kinases can also act as oncogenes, but in comparison with tyrosine protein kinases, their contribution is relatively modest.61,62

Soon after its discovery in 1960, SV40 was found as a contaminant in poliovirus vaccine. Clearly, this was a cause of concern. Already, more than 98 million Americans (and countless more throughout the world) had received

one or more doses of the vaccine during the period 1955–63. Could immunization cause cancer? As luck turned out, nothing came of it. No widespread incidence of SV40 infection in the population, no increase

of tumours, nor any direct role for SV40 in human cancer.63