Adult human sarcomas. I. Basic science

Abstract

When connective tissue undergoes malignant transformation, glioblastomas and sarcomas arise. However, the ancient biochemical mechanisms, which are now operational in sarcomas distorted by mutations and gene fusions in misaligned chromosomes, were originally acquired by those cells that emerged during the Cambrian explosion. Preserved throughout evolution up to the genus Homo, these mechanisms dictate the apoptosis- and senescence-resistant immortality of malignant cells. A ‘retroviral paradox’ distinguishes human sarcomas from those of the animal world. In contrast to the retrovirally induced sarcomatous transformation of animal (avian, murine, feline and simian) cells, human sarcomas have so far failed to yield a causative retroviral isolate. However, the proto-oncogenes/oncogenes transduced from their host cells by retroviruses of animals are the same that are active in human sarcomas. Since the encoded oncoproteins arise after birth, they are recognized frequently by the immune system of the host. Immune lymphocytes that kill autologous sarcoma cells in vitro commonly fail to do so in vivo. Sarcoma vaccines generate immune T- and natural killer cell reactions; even when vaccinated patients do not show a clinical response, their tumors become more sensitive to chemotherapy. The aim of this review is to lay a solid molecular biological foundation for the conclusion that targeting the sarcoma oncogenes will result in regression of the disease.

Keywords::

• chromosomal translocations
• cytotoxic lymphocytes
• fusion oncogenes
• fusion oncoproteins
• HHV-8
• retroviral isolates
• TREG & CTL/NK cell antagonists

Acknowledgements

The author expresses his thanks to assistant professor Dr H David Kay, to research fellow Dr Harikishan Thota and to chief medical technologists Jerry Cabiness and Jim Romero for expert and reliable assistance in the experiments carried out at the Section of Clinical Tumor Virology and Immunology, Department of Medicine, The University of Texas MD Anderson Hospital, Houston, TX, USA, from 1965–1979. The author is very much obliged for help with electron microscopy to Professor Dr Ferenc Györkey; and for help with immunofluorescence studies to Dr Eiichi Shirato.

Notes

*Musculoaponeurotic fibrosarcoma; c-maf translocted in multiple myeloma t(14;16)(q32;q23).

^‡Fusion oncogene t(9q34;22q11) encoding fusion oncoprotein p210ABL/BCR in Ph + CML; c-abl/bcr is targeted by imatinib mesylate in CML. ^§Kaposi sarcoma fibroblast growth factor.

^¶Macrophage colony stimulating factor receptor (M-CSF1R) gp165c-fms→gp140c-fms.

^#CD117 receptor of stem cell factor targeted by imatinib mesylate in GIST.

**Platelet-derived growth factor (PDGF)-β) 110 kD protein for para- & autocrine circuits; autocrine circuit of PDGF→PDGF-R in dermatofibrosarcoma protuberans with translocation t(17;22)(q22;q13) targeted by imatinib mesylate. PDGFβ-chain gene c-sis mapped to 22q13.

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Akt: The directly transforming retrovirus AKT8 carries the genomic sequence v-act, which takes its origin from the genome of the murine host’s c-act. The human Akt protein is a serine-threonine kinase with homology to the src (Rous sarcoma) oncoproteins; bFGF: Basic fibroblast growth factor; CMV: Cytomegalovirus; EBV: Epstein–Barr virus; HHV: Human herpesvirus; hSNF5: Chromatin remodeling complex gene also mutated in childhood rhabdomyosarcoma (Nature 394, 203 (1998); J. Virol. 687, 519 (2006)); IFN: Interferon; IGF: Insulin growth factor; LANA: Latency-associated antigen; MEK/ERK: MAPK and extracellular signal-regulated kinase kinase; MIF: Macrophage inflammatory factor; ORF: Open reading frame; PDGF: Platelet-derived growth factor; PI3K: Phosphatidyl inositol kinase; PPAR: Peroxisome proliferator-activated receptor; siRNA: Small inhibitory RNA; NF: Nuclear factor: VEGF: Vascular endothelial growth factor; v-IRF: Viral interferon regulatory factor; WT: Wilms tumor.

EM: Electron microscopy; JSRV: Jaagsiekte sheep retrovirus (related to human bronchioalveolar carcinoma?); KS: Karposi’s sarcoma; LINE/SINE: Long (6 kbp) and short (300 bp) interspersed nuclear elements; LTR: Long terminal repeat; MMTV: Mouse mammary tumor (Bittner) virus; RAG: Recombination (segmental rearrangements) activating genes of ancient retrotransposon origin.