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Review
. 2017 Jan;108(1):5-11.
doi: 10.1111/cas.13116. Epub 2017 Jan 23.

Mourning Dr. Alfred G. Knudson: the two-hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex

Okio Hino  1   2 , Toshiyuki Kobayashi  1   2
Affiliations
Review

Mourning Dr. Alfred G. Knudson: the two-hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex

Okio Hino et al. Cancer Sci. 2017 Jan.

Abstract

On July 10, 2016, Alfred G. Knudson, Jr., MD, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two-hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor-predisposing syndromes. To understand the molecular mechanism of two-hit-initiated tumorigenesis, Knudson used an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of Tsc2 germline mutations, the Eker rat became a model for tuberous sclerosis complex (TSC), a familial tumor-predisposing syndrome. Animal models, including the fly, have greatly contributed to TSC research. Because the product of the TSC2/Tsc2 gene (tuberin) together with hamartin, the product of another TSC gene (TSC1/Tsc1), suppresses mammalian/mechanistic target of rapamycin complex 1 (mTORC1), rapalogs have been used as therapeutic drugs for TSC. Although significant activity of these drugs has been reported, there are still problems such as recurrence of residual tumors and adverse effects. Recent studies indicate that there are mTORC1-independent signaling pathways downstream of hamartin/tuberin, which may represent new therapeutic targets. The establishment of cellular models, such as pluripotent stem cells with TSC2/Tsc2 gene mutations, will facilitate the understanding of new aspects of TSC pathogenesis and the development of novel treatment options. In this review, we look back at the history of Knudson and animal models of TSC and introduce recent progress in TSC research.

Keywords: Eker rat; retinoblastoma; tuberous sclerosis complex; tumor suppressor gene; two-hit hypothesis.

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Figures

Figure 1
Figure 1
Memorial figures for Knudson. (a) The cover of the special issue of Genes Chromosomes & Cancer on Knudson's 80th birthday (December 2003; vol. 38, issue 4, with the permission of John Wiley & Sons, Inc.). (b) The plot from which Knudson proposed the two‐hit hypothesis (Ref. 2, with the permission of the National Academy of Sciences, USA).
Figure 2
Figure 2
mTORC1‐dependent‐ and ‐independent pathways downstream of hamartin/tuberin. There are two categories of mTORC1‐independent pathways according to their dependence on Rheb. Only representative pathways are shown.
Figure 3
Figure 3
Haploinsufficiency‐ and two‐hit‐initiated pathologies in tuberous sclerosis complex (TSC). Germline mutations (1st hit) cause neuropsychiatric symptoms during infancy without a 2nd hit. Other lesions, such as cortical tubers in brain may be caused by haploinsufficiceny of TSC genes. The majority of tumorous lesions develop after two hits of TSC genes. In animal models, tumorigenesis without a 2nd hit has been reported. Although not depicted in this figure, there are interactions between two‐hit‐initiated tumorous cells and surrounding non‐tumorous cells to form lesions.
Figure 4
Figure 4
A model of differentiation abnormalities in tuberous sclerosis complex (TSC) using pluripotent stem cells (PSCs). There are tissue‐specific mechanisms in the pathogenesis of TSC. Modeling of differentiation abnormalities related to TSC (in the box delineated by dotted lines) will be useful to explore the mechanism of pathogenesis and to establish high‐throughput screening systems. Upon differentiation, compared with wild‐type cells (not depicted in this figure) homozygous PSCs mutant for TSC genes (TSC1 −/− or 2 −/−) may show differentiation abnormalities with or without aberrant proliferation in some specific lineages. In the case of neurons, heterozygous cells (TSC1 +/− or 2 +/−) may cause functional defects related to neuropsychiatric symptoms of TSC. For neuronal differentiation of human TSC2‐mutant ES cells, refer to Costa, V, et al.80
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