Targeting the Mechanisms of Resistance to Chemotherapy and Radiotherapy with the Cancer Stem Cell Hypothesis

Morrison, Ryan G.; Schleicher, Stephen M.; Sun, Yeying; Niermann, Kenneth J.; Kim, Sungjune; Spratt, Daniel E.; Chung, Christine H.; Lü, Bo

doi:10.1155/2011/941876

Cited by 204 publications

(153 citation statements)

References 117 publications

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“…Most recent studies have highlighted the heterogeneity of ovarian tumors, and the current understanding is that inherently chemoresistant cancer stem cells that are not removed by surgery and survive first-line chemotherapy are able to recreate the tumor and cause disease recurrence (4)(5)(6)(7)(8). Our group and others have demonstrated that within the heterogeneous tumor, CD44…”

Section: Introductionmentioning

confidence: 90%

TRX-E-002-1 Induces c-Jun–Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo

Alvero

Heaton²,

Lima

et al. 2016

Molecular Cancer Therapeutics

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Chemoresistance is a major hurdle in the management of patients with epithelial ovarian cancer and is responsible for its high mortality. Studies have shown that chemoresistance is due to the presence of a subgroup of cancer cells with stemness properties and a high capacity for tumor repair. We have developed a library of super-benzopyran analogues to generate potent compounds that can induce cell death in chemoresistant cancer stem cells.

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Section: Introductionmentioning

confidence: 90%

TRX-E-002-1 Induces c-Jun–Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo

Alvero

Heaton²,

Lima

et al. 2016

Molecular Cancer Therapeutics

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“…It is well known that most solid tumors contain a distinct subpopulation of cancer stem cells (CSCs), which represent the source for tissue renewal, hold malignant potential and can be responsible for therapy resistance [3][4][5][6], and it has been suggested that a successful cure of cancer should requires eradication of CSCs [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells

Fiore

Marcatti

Drago-Ferrante

et al. 2014

Bone

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Osteosarcoma is a highly metastatic tumor affecting adolescents, for which there is no second-line chemotherapy. As suggested for most tumors, its capability to overgrow is probably driven by cancer stem cells (CSCs), and finding new targets to kill CSCs may be critical for improving patient survival. TP53 is the most frequently mutated tumor suppressor gene in cancers and mutant p53 protein (mutp53) can acquire gain of function (GOF) strongly contributing to malignancy. Studies thus far have not shown p53-GOF in osteosarcoma. Here, we investigated TP53 gene status/role in 3AB-OS cells-a highly aggressive CSC line previously selected from human osteosarcoma MG63 cells-to evaluate its involvement in promoting proliferation, invasiveness, resistance to apoptosis and stemness. By RT-PCR, methylation-specific PCR, fluorescent in situ hybridization, DNA sequence, western blot and immunofluorescence analyses, we have shown that-in comparison with parental MG63 cells where TP53 gene is hypermethylated, rearranged and in single copy-in 3AB-OS cells, TP53 is unmethylated, rearranged and in multiple copies, and mutp53 (p53-R248W/P72R) is post-translationally modified and with nuclear localization. p53-R248W/P72R-knockdown by short-interfering RNA reduced the growth and replication rate of 3AB-OS cells, markedly increasing cell cycle inhibitor levels and sensitized 3AB-OS cells to TRAILinduced apoptosis by DR5 up-regulation; moreover, it strongly decreased the levels of stemness and invasiveness genes. We have also found that the ectopic expression of p53-R248W/P72R in MG63 cells promoted cancer stemlike features, as high proliferation rate, sphere formation, clonogenic growth, high migration and invasive ability; furthermore, it strongly increased the levels of stemness proteins. Overall, the findings suggest the involvement of p53-R248W/P72R at the origin of the aberrant characters of the 3AB-OS cells with the hypothesis that its GOF can be at the root of the dedifferentiation of MG63 cells into CSCs.

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“…Several of these characteristics are believed to be important in the resistance of CSC to traditional chemotherapy and radiation. 63,73,[79][80][81][82][83][84] The ability of CSC to leverage these characteristics to better handle environmental stresses and genotoxic damage potentially explains the disconnect between therapeutic response (ie, tumor burden reduction) and overall survival in the clinic. Tumors can all but be eradicated; however, if CSC persist, tumors will inevitably recur and are likely to be more aggressive given the genotoxic insults survived.…”

Section: Pdx Models and The Resurrection Of Tumor Stem Cellsmentioning

confidence: 99%

Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century

Williams

Anderson

Santaguida

et al. 2013

Laboratory Investigation

165

166

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Cancer is a heterogeneous disease manifest in many forms. Tumor histopathology can differ significantly among patients and cellular heterogeneity within tumors is common. A primary goal of cancer biologists is to better understand tumorigenesis and cancer progression; however, the complex nature of tumors has posed a substantial challenge to unlocking cancer's secrets. The cancer stem cell (CSC) paradigm for the pathobiology of solid tumors appropriately acknowledges phenotypic and functional tumor cell heterogeneity observed in solid tumors and accounts for the disconnect between drug approval based on response and the general inability of approved therapies to meaningfully impact survival due to their failure to eradicate these most important of cellular targets. First proposed to exist decades ago, CSC have only recently begun to be precisely identified due to technical advancements that facilitate identification, isolation, and interrogation of distinct tumor cell subpopulations with differing ability to form and perpetuate tumors. Precise identification of CSC populations and the complete hierarchy of cells within solid tumors will facilitate more accurate characterization of patient subtypes and ultimately contribute to more personalized and effective therapies. Rapid advancement in the understanding of tumor biology as it exists in patients requires cooperation among institutions, surgeons, pathologists, cancer biologists and patients alike, primarily because this translational research is best done with patient-derived tissue grown in the xenograft setting as patient-derived xenografts. This review calls for a broader change in the approaches taken to study cancer pathobiology, highlights what implications the CSC paradigm has for pathologists and cancer biologists alike, and calls for greater collaboration between institutions, physicians and scientists in order to more rapidly advance our collective understanding of cancer.

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Targeting the Mechanisms of Resistance to Chemotherapy and Radiotherapy with the Cancer Stem Cell Hypothesis

Cited by 204 publications

References 117 publications

TRX-E-002-1 Induces c-Jun–Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo

TRX-E-002-1 Induces c-Jun–Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo

Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells

Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century

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