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Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many p... more Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many patients relapse over time. At least two major explanations exist for these observations. The first is that all cancer cells acquire resistance, resulting in decreased overall sensitivity to therapy over time. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to be similar before and after treatment. The second explanation is that a rare subpopulation of cells with tumorigenic potential is intrinsically resistant to therapy. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to increase after treatment. Analogous to the propensity of dandelion roots to regenerate weeds, regrowth of tumors from an intrinsically chemotherapy-resistant subpopulation has been termed the "dandelion hypothesis" ( 2 ). Consistent with this hypothesis, we have previously shown ( 3 ) that the gene expression pattern of residual tumor cells surviving after treatment is

Journal of The National Cancer Institute, 2008

Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many p... more Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many patients relapse over time. At least two major explanations exist for these observations. The first is that all cancer cells acquire resistance, resulting in decreased overall sensitivity to therapy over time. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to be similar before and after treatment. The second explanation is that a rare subpopulation of cells with tumorigenic potential is intrinsically resistant to therapy. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to increase after treatment. Analogous to the propensity of dandelion roots to regenerate weeds, regrowth of tumors from an intrinsically chemotherapy-resistant subpopulation has been termed the "dandelion hypothesis" ( 2 ). Consistent with this hypothesis, we have previously shown ( 3 ) that the gene expression pattern of residual tumor cells surviving after treatment is

Molecular and Cellular Biology, 2008

The transforming growth factor ␤ (TGF␤) family has critical roles in the regulation of fertility.... more The transforming growth factor ␤ (TGF␤) family has critical roles in the regulation of fertility. In addition, the pathogenesis of some human cancers is attributed to misregulation of TGF␤ function and SMAD2 or SMAD4 mutations. There are limited mouse models for the BMP signaling SMADs (BR-SMADs) 1, 5, and 8 because of embryonic lethality and suspected genetic redundancy. Using tissue-specific ablation in mice, we deleted the BR-SMADs from somatic cells of ovaries and testes. Single conditional knockouts for Smad1 or Smad5 or mice homozygous null for Smad8 are viable and fertile. Female double Smad1 Smad5 and triple Smad1 Smad5 Smad8 conditional knockout mice become infertile and develop metastatic granulosa cell tumors. Male double Smad1 Smad5 conditional knockout mice are fertile but demonstrate metastatic testicular tumor development. Microarray analysis indicated significant alterations in expression of genes related to the TGF␤ pathway, as well as genes involved in infertility and extracellular matrix production. These data strongly implicate the BR-SMADs as part of a critical developmental pathway in ovaries and testis that, when disrupted, leads to malignant transformation.

Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many p... more Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many patients relapse over time. At least two major explanations exist for these observations. The first is that all cancer cells acquire resistance, resulting in decreased overall sensitivity to therapy over time. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to be similar before and after treatment. The second explanation is that a rare subpopulation of cells with tumorigenic potential is intrinsically resistant to therapy. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to increase after treatment. Analogous to the propensity of dandelion roots to regenerate weeds, regrowth of tumors from an intrinsically chemotherapy-resistant subpopulation has been termed the "dandelion hypothesis" ( 2 ). Consistent with this hypothesis, we have previously shown ( 3 ) that the gene expression pattern of residual tumor cells surviving after treatment is

Journal of The National Cancer Institute, 2008

Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many p... more Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many patients relapse over time. At least two major explanations exist for these observations. The first is that all cancer cells acquire resistance, resulting in decreased overall sensitivity to therapy over time. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to be similar before and after treatment. The second explanation is that a rare subpopulation of cells with tumorigenic potential is intrinsically resistant to therapy. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to increase after treatment. Analogous to the propensity of dandelion roots to regenerate weeds, regrowth of tumors from an intrinsically chemotherapy-resistant subpopulation has been termed the "dandelion hypothesis" ( 2 ). Consistent with this hypothesis, we have previously shown ( 3 ) that the gene expression pattern of residual tumor cells surviving after treatment is

Molecular and Cellular Biology, 2008

Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many p... more Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many patients relapse over time. At least two major explanations exist for these observations. The first is that all cancer cells acquire resistance, resulting in decreased overall sensitivity to therapy over time. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to be similar before and after treatment. The second explanation is that a rare subpopulation of cells with tumorigenic potential is intrinsically resistant to therapy. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to increase after treatment. Analogous to the propensity of dandelion roots to regenerate weeds, regrowth of tumors from an intrinsically chemotherapy-resistant subpopulation has been termed the "dandelion hypothesis" ( 2 ). Consistent with this hypothesis, we have previously shown ( 3 ) that the gene expression pattern of residual tumor cells surviving after treatment is

Journal of The National Cancer Institute, 2008

Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many p... more Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many patients relapse over time. At least two major explanations exist for these observations. The first is that all cancer cells acquire resistance, resulting in decreased overall sensitivity to therapy over time. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to be similar before and after treatment. The second explanation is that a rare subpopulation of cells with tumorigenic potential is intrinsically resistant to therapy. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to increase after treatment. Analogous to the propensity of dandelion roots to regenerate weeds, regrowth of tumors from an intrinsically chemotherapy-resistant subpopulation has been termed the "dandelion hypothesis" ( 2 ). Consistent with this hypothesis, we have previously shown ( 3 ) that the gene expression pattern of residual tumor cells surviving after treatment is

Molecular and Cellular Biology, 2008

The transforming growth factor ␤ (TGF␤) family has critical roles in the regulation of fertility.... more The transforming growth factor ␤ (TGF␤) family has critical roles in the regulation of fertility. In addition, the pathogenesis of some human cancers is attributed to misregulation of TGF␤ function and SMAD2 or SMAD4 mutations. There are limited mouse models for the BMP signaling SMADs (BR-SMADs) 1, 5, and 8 because of embryonic lethality and suspected genetic redundancy. Using tissue-specific ablation in mice, we deleted the BR-SMADs from somatic cells of ovaries and testes. Single conditional knockouts for Smad1 or Smad5 or mice homozygous null for Smad8 are viable and fertile. Female double Smad1 Smad5 and triple Smad1 Smad5 Smad8 conditional knockout mice become infertile and develop metastatic granulosa cell tumors. Male double Smad1 Smad5 conditional knockout mice are fertile but demonstrate metastatic testicular tumor development. Microarray analysis indicated significant alterations in expression of genes related to the TGF␤ pathway, as well as genes involved in infertility and extracellular matrix production. These data strongly implicate the BR-SMADs as part of a critical developmental pathway in ovaries and testis that, when disrupted, leads to malignant transformation.

Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many p... more Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many patients relapse over time. At least two major explanations exist for these observations. The first is that all cancer cells acquire resistance, resulting in decreased overall sensitivity to therapy over time. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to be similar before and after treatment. The second explanation is that a rare subpopulation of cells with tumorigenic potential is intrinsically resistant to therapy. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to increase after treatment. Analogous to the propensity of dandelion roots to regenerate weeds, regrowth of tumors from an intrinsically chemotherapy-resistant subpopulation has been termed the "dandelion hypothesis" ( 2 ). Consistent with this hypothesis, we have previously shown ( 3 ) that the gene expression pattern of residual tumor cells surviving after treatment is

Journal of The National Cancer Institute, 2008

Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many p... more Conventional chemotherapies are initially effective in controlling tumor growth ( 1 ), yet many patients relapse over time. At least two major explanations exist for these observations. The first is that all cancer cells acquire resistance, resulting in decreased overall sensitivity to therapy over time. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to be similar before and after treatment. The second explanation is that a rare subpopulation of cells with tumorigenic potential is intrinsically resistant to therapy. In this case, the relative proportion of cells in residual tumors with tumorigenic properties would be expected to increase after treatment. Analogous to the propensity of dandelion roots to regenerate weeds, regrowth of tumors from an intrinsically chemotherapy-resistant subpopulation has been termed the "dandelion hypothesis" ( 2 ). Consistent with this hypothesis, we have previously shown ( 3 ) that the gene expression pattern of residual tumor cells surviving after treatment is

Molecular and Cellular Biology, 2008