Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine kinases, there is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumour types, and clinical reagents that specifically target the FGFs or FGF receptors are being developed. Although FGF signalling can drive tumorigenesis, in different contexts FGF signalling can mediate tumour protective functions; the identification of the mechanisms that underlie these differential effects will be important to understand how FGF signalling can be most appropriately therapeutically targeted.

Fibroblast growth factor signalling: from development to cancer

The search for genetic damage in neoplastic cells now occupies a central place in cancer research. Diverse examples of such damage are in hand, and they in turn hint at biochemical explanations for neoplastic growth. The way may be open to solve the riddles of how normal cells govern their replication and why cancer cells do not.

https://science.sciencemag.org/content/sci/235/4786/305.full.pdf

The molecular genetics of cancer

A key feature in adeno-associated virus (AAV) replication is efficient integration of the viral genome into host cell DNA to establish latency when helper virus is absent. The steps involved in this process remain largely uncharacterized, even though AAV integration was first documented 20 years ago. Using a protein--DNA binding method we isolated AAV--cellular junction DNA sequences. The cellular component hybridized to a single restriction fragment in the virus-free parental cell line, and also co-migrated with AAV-specific sequences in numerous latently infected cell lines. Analysis of somatic cell hybrids indicated that this cellular sequence maps to the distal portion of the q arm of human chromosome 19. In situ hybridization of AAV DNA to chromosomes from latently infected cells confirms the physical location of AAV integrations to be q13.4-ter of chromosome 19. Sequence analysis of several independent integration sites shows breakpoints occurring within a 100 bp cellular region. This non-pathogenic parvovirus thus appears to establish viral latency by integrating its DNA specifically into one chromosomal region. Such specific integration is so far unique among the eukaryotic DNA viruses. The incorporation of site-specific integration into AAV vector schemes should make this vector system attractive for human gene therapy approaches.

Targeted integration of adeno-associated virus (AAV) into human chromosome 19.

DEFINITIONS OF CELLULAR ONCOGENES 555 c-one's: The Proto-Oncogenic Progenitors of Retroviral Oncogenes . . . . . . . . . . . . . . . . . . . 555 Identification of Cellular Oncogenes by Functional Tests for Dominant Mutations 558 Using Genetic Rearrangements to Identify Oncogenes . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562 Proviral insertions can activate expression oj cellular proto-oncogenes 563 Oncogenes at translocation breakpoints. . ... . . . . ..... 566 Oncogenes in amplified DNA ..... . . ...... ........ . . . ..... ........ . . . .. . . ....... ... . . . . . .. . 567 MOLECULAR PROFILES OF ACTIVATED ONCOGENES 570 Base Substitutions in Mutant ras Alleles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 Insertionally Mutated c-myc Loci. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574 Locations oj proviruses 574 Additional mutations in proviraUy mutated loci ...... . . .... 576 Characteristics of Other Proviral Insertion Mutations in Proto-Oncogenes 578 Structural and Functional Properties of Translocation Breakpoints near Cellular Oncogenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581 General Jeatures oj c-myc; immunoglobulin gene translocations . . . . . . . . . . . . . . . . . . . . 581 Specific examples of c-myc; Ig translocations in PC and BL lines ........ . . . . . . . . . 583 The Phi chromosome .. . .. ....... . . . . . . . ..... . .. . ... . . . . . . . . ... . . . . . . . ... .. .. .. 586 Other translocations and rearrangements in B cell tumor lines . . . . . . . . . . . . . . . . . . . . . 587 Structural Features oj Amplified Oncogenes . ...... ..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587 FROM c-onc TO v-onc: COLLUSION OF MUTATIONAL MECHANISMS....... 588 The Favored Model Jar Transduction of Oncogenes . .. . . 590 The Functional Significance of Diff erences Between c-onc' s and v-onc' s 592 INACTIVATION OF INTEGRATED v-onc GENES: A SAMPLER OF MUTATIONAL MECHANISMS 593

The Molecular Genetics of Cellular Oncogenes

Expression of the proto-oncogene int-1 is restricted to specific neural cells in the developing mouse embryo.

Concerted activation of two potential proto-oncogenes in carcinomas induced by mouse mammary tumour virus

Concerted activation of two potential proto-oncogenes in carcinomas induced by mouse mammary tumour virus.

There is now good evidence that the induction of mammary carcinomas by mouse mammary tumour virus (MMTV) involves provirus activation of specific cellular genes. Thus, a high percentage of virally induced tumours contain an acquired MMTV provirus in either of two defined integration regions, termed int-1 and int-2, and provirus insertion is accompanied by expression of specific RNA transcripts from these regions1–4. We show here that in some recurring, pregnancy-dependent mammary tumours provirus integration within int-2 has already occurred at the earliest appearance of the tumour and may therefore represent an important step in the development of neoplasia. As judged by the distribution of the acquired MMTV proviruses, the tumours recurring at any one site represent the same clonal population of cells as the original tumour and remain clonal during cycles of proliferation and regression, including the transition to hormone-independent status. These data suggest that either the expression of the int-2 locus or the function of this putative oncogene must remain responsive to hormones and that some additional event must be responsible for the transition to autonomous growth.

Audrey E. Lee

Papers

Concerted activation of two potential proto-oncogenes in carcinomas induced by mouse mammary tumour virus.

Activation of cellular gene by mouse mammary tumour virus may occur early in mammary tumour development