Fishing for the origins of cancer: Figure 1.

Merlino, Glenn; Khanna, Chand

doi:10.1101/gad.1563707

Cited by 24 publications

(23 citation statements)

References 36 publications

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“…The two major histological types of RMS tumors are alveolar RMS, the more aggressive subtype defined by specific translocations involving the genes paired box 3 (PAX3) or paired box 7 (PAX7) and forkhead box O1 (FKHR also known as FOXO1a), and embryonal RMS, which is less genetically well defined (18). These tumors differ in occurrence, location, patient age, and, most importantly, prognosis.…”

Section: Myomir-1/206 Reexpression Effectively Targets Rmsmentioning

confidence: 99%

MicroRNA reexpression as differentiation therapy in cancer

Mishra¹,

Merlino²

2009

J. Clin. Invest.

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Since their discovery in the early 2000s, microRNAs (miRNAs) and their penchant for RNA interference have taken the scientific community by storm, working their way into virtually every corner of biological inquiry. The very nature of their action, the ability to simultaneously extinguish the expression of a multitude of genes and negate their functions, immediately suggested therapeutic promise. In this issue of the JCI, a step toward the realization of this promise is described. Taulli et al. demonstrate that the miRNAs miR-1/ miR-206, which are routinely lost in advanced, poorly differentiated rhabdomyosarcoma (RMS) but characteristically expressed in the mature skeletal muscle from which these tumors arise, restore the myogenic differentiation program and block the tumorigenic phenotype (see the related article beginning on page 2366). Their data support the notion that these small RNAs, effectively functioning as "micro-sheriffs" by restoring myogenic law and order, hold substantial clinical potential as differentiation therapy for RMS and perhaps other solid tumors. miRNA reexpression therapy constitutes a novel approach to handcuff oncogenes and arrest tumor development.

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Section: Myomir-1/206 Reexpression Effectively Targets Rmsmentioning

confidence: 99%

MicroRNA reexpression as differentiation therapy in cancer

Mishra¹,

Merlino²

2009

J. Clin. Invest.

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“…In the case of embryonal rhabdomyosarcoma (EMRS), the generation of a zebrafish model in which the disease is induced by RAS oncogenic activation has allowed the identification of a serially transplantable CSC that shares the gene signature of muscle satellite cells. (33) On the basis of this and other evidences, it has been postulated (34,35) that strong oncogenic events such as sarcoma-inducing chromosomal translocations will only be tolerated in permissive cells such as MSC. MLL-ENL (39) or MLL-GAS7, (40) must be able to confer stemlike properties to more-committed target cells, since they can generate CSCs when transfected into committed hematopoietic progenitors.…”

Section: Cscs In Sarcomasmentioning

confidence: 99%

The theoretical basis of cancer‐stem‐cell‐based therapeutics of cancer: can it be put into practice?

2007

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SummaryIn spite of the advances in our knowledge of cancer biology, most cancers remain not curable with present therapies. Current treatments consider cancer as resulting from uncontrolled proliferation and are non-specific. Although they can reduce tumour burden, relapse occurs in most cases. This was long attributed to incomplete tumour elimination, but recent developments indicate that different types of cells contribute to the tumour structure, and that the tumour's cellular organization would be analogous to that of a normal tissue, with a main mass of differentiating cells sensitive to antiproliferative agents, together with a small percentage of quiescent, resistant stem cells responsible for replenishing the tumour: the Cancer Stem Cells (CSCs). AntiCSCs targeted therapeutic agents would prevent tumour regeneration. New mouse models tailored to exploit this novel concept will be critical to develop CSC-based anti-cancer therapies. Here we review the biological basis and the therapeutic implications of the stem-cell model of cancer.

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“…In contrast, cells which are already committed to a lineage (for example, myogenic stem cells or committed satellite cells in skeletal muscle) are restricted in their permissiveness, and may tolerate only weak oncogenic events (Merlino and Khanna, 2007). Assuming that this hypothesis is correct and that loss of Ptch function is a highly potent oncogenic event, it is possible that an uncommitted cell, for example, mesodermal cells derived from the presomitic mesoderm, are more poised to develop ERMS in response to the Ptch mutation than more differentiated, for example, a Myf5-expressing myogenic progenitors.…”

Section: Discussionmentioning

confidence: 99%

Uncommitted precursor cells might contribute to increased incidence of embryonal rhabdomyosarcoma in heterozygous Patched1-mutant mice

et al. 2011

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Embryonal rhabdomyosarcoma (ERMS) is a tumor of the skeletal muscle in children and is frequently initiated by heterozygous germline mutations in the Hedgehog (Hh) receptor Patched1 (Ptch), both in humans and mice. Using a conditional knock-out strategy in Ptch flox/ þ mice, we demonstrate that early embryonic stages are more susceptible to ERMS development than later stages and that cells normally not committed to undergo myogenesis at this stage represent the major source of ERMS. We found that deletion of a single copy of the Ptch allele at E9.5 using the ubiquitously active Rosa26CreERT2 resulted in a tumor incidence of 88% but reached only 44% and 12% when the Ptch allele was inactivated at E11.5 and E13.5, respectively. Induction of the Ptch mutation at E9.5 did also significantly shorten ERMS-free survival and increased tumor multiplicity compared with tumor induction at E11.5 and E13.5. Interestingly, we observed a more that 10-fold reduction of ERMS incidence when the Ptch mutation was specifically introduced in Myf5-expressing cells, which is the myogenic factor expressed in all muscle cells at E9.5. We conclude that Myf5-negative cells are more susceptible to ERMS development than Myf5-positive embryonic precursors. As the propensity to undergo tumorigenic transformation declined with age, concomitant with the increase of stably committed muscle cells, it seems likely that the Ptch mutation favors tumor formation in progenitor cells, which have not yet acquired a muscle cell fate.

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Fishing for the origins of cancer: Figure 1.

Cited by 24 publications

References 36 publications

MicroRNA reexpression as differentiation therapy in cancer

MicroRNA reexpression as differentiation therapy in cancer

The theoretical basis of cancer‐stem‐cell‐based therapeutics of cancer: can it be put into practice?

Uncommitted precursor cells might contribute to increased incidence of embryonal rhabdomyosarcoma in heterozygous Patched1-mutant mice

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