Reprogramming of prostate cancer‐associated stromal cells to embryonic stem‐like

Vêncio, Eneida Franco; Nelson, Angelique M.; Cavanaugh, Christopher; Ware, Carol B.; Milller, Daniel G.; García, J. C.; Vêncio, Ricardo Zorzetto Nicoliello; Loprieno, Michelle A.; Liu, Alvin Y.

doi:10.1002/pros.22497

Cited by 25 publications

(36 citation statements)

References 37 publications

(68 reference statements)

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“…Cells without CD59 might, therefore, be resistant to the effect of AGR2. Another possible future study could determine the effect of secreted AGR2 on stem cells such as the induced pluripotent stem cells generated from reprogramming of prostate stromal cells [35], given its function in organ regeneration.…”

Section: Discussionmentioning

confidence: 99%

Cancer-secreted AGR2 induces programmed cell death in normal cells

et al. 2016

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Anterior Gradient 2 (AGR2) is a protein expressed in many solid tumor types including prostate, pancreatic, breast and lung. AGR2 functions as a protein disulfide isomerase in the endoplasmic reticulum. However, AGR2 is secreted by cancer cells that overexpress this molecule. Secretion of AGR2 was also found in salamander limb regeneration. Due to its ubiquity, tumor secretion of AGR2 must serve an important role in cancer, yet its molecular function is largely unknown. This study examined the effect of cancer-secreted AGR2 on normal cells. Prostate stromal cells were cultured, and tissue digestion media containing AGR2 prepared from prostate primary cancer 10-076 CP and adenocarcinoma LuCaP 70CR xenograft were added. The control were tissue digestion media containing no AGR2 prepared from benign prostate 10-076 NP and small cell carcinoma LuCaP 145.1 xenograft. In the presence of tumor-secreted AGR2, the stromal cells were found to undergo programmed cell death (PCD) characterized by formation of cellular blebs, cell shrinkage, and DNA fragmentation as seen when the stromal cells were UV irradiated or treated by a pro-apoptotic drug. PCD could be prevented with the addition of the monoclonal AGR2-neutralizing antibody P3A5. DNA microarray analysis of LuCaP 70CR media-treated vs. LuCaP 145.1 media-treated cells showed downregulation of the gene SAT1 as a major change in cells exposed to AGR2. RT-PCR analysis confirmed the array result. SAT1 encodes spermidine/spermine N1-acetyltransferase, which maintains intracellular polyamine levels. Abnormal polyamine metabolism as a result of altered SAT1 activity has an adverse effect on cells through the induction of PCD.

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Section: Discussionmentioning

confidence: 99%

Cancer-secreted AGR2 induces programmed cell death in normal cells

et al. 2016

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“…8,23e26 Lin28 controls the biogenesis of let-7 miRNAs 27,28 and is one of the pluripotency factors that are responsible for the reprogramming of differentiated cells to stem cell like. 29 In this study, we showed that Lin28 is overexpressed in human CaP compared to benign tissues, promotes growth of human CaP cells in vitro, and enhances growth of CaP xenografts. To our knowledge, this is the first report demonstrating the role of Lin28 in CaP cell proliferation and the ability of Lin28 to promote prostate tumor growth.…”

Section: Discussionmentioning

confidence: 65%

1322 Lin28 Promotes Growth of Prostate Cancer Cells and Activates the Androgen Receptor

et al. 2013

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Prostate cancer (CaP) progresses to a castration-resistant state assisted by multifold molecular changes, most of which involve activation of the androgen receptor (AR). Having previously demonstrated the importance of the Lin28/let-7/Myc axis in CaP, we tested the hypothesis that Lin28 is overexpressed in CaP and that it activates AR and promotes growth of CaP cells. We analyzed human clinical CaP samples for the expression of Lin28 by quantitative real-time RT-PCR, Western blot analysis, and IHC. Growth characteristics of CaP cell lines transiently and stably expressing Lin28 were examined. The clonogenic ability of CaP cells expressing Lin28 was determined by colony formation and soft agar assays. Increase in expression of AR and subsequent increase in transcription of AR-target genes were analyzed by quantitative real-time RT-PCR, luciferase assays, and ELISA. LNCaP cells stably expressing Lin28 were injected into nude mice, and tumorigenesis was monitored. We found that Lin28 is overexpressed in clinical CaP compared to benign prostates. Overexpression of Lin28 enhanced, while down-regulation reduced, growth of CaP cells. Lin28 enhanced the ability of CaP cells to form colonies in anchorage-dependent and anchorage-independent conditions. LNCaP cells stably expressing Lin28 exhibited significantly higher tumorigenic ability in vivo. Lin28 induced expression of the AR and its target genes such as PSA and NKX3.1. Collectively, our findings demonstrate a novel role for Lin28 in CaP development and activation of the AR axis. (Am J Pathol 2013, 183: 288e295; http://dx

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“…In addition, it was reported that MAGEA2 binds with the p53 tumour suppressor protein to repress p53 transcriptional activity by recruiting the histone deacetylase HDAC3 . In stem cell biology, it is well known that undifferentiated human embryonic stem cells express various MAGEA family proteins, including MAGEA2 . When human embryonic stem cells were differentiated into EBs and teratomas, the expression levels of MAGEA family members were spontaneously regulated .…”

Section: Introductionmentioning

confidence: 99%

“…18,23 In stem cell biology, it is well known that undifferentiated human embryonic stem cells express various MAGEA family proteins, including MAGEA2. 24,25 When human embryonic stem cells were differentiated into EBs and teratomas, the expression levels of MAGEA family members were spontaneously regulated. 26 Therefore, many biologists have predicted that MAGEA proteins are highly expressed and play a critical role in iPS cells, but their specific functions have remained unknown.…”

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confidence: 99%

Critical roles of hMAGEA2 in induced pluripotent stem cell pluripotency, proliferation, and differentiation

Park

Sung

Jeong

et al. 2017

Cell Biochemistry & Function

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Induced pluripotent stem (iPS) cells are important for clinical application and stem cell research. Although human melanoma-associated antigen A2 (hMAGEA2) expression is known to affect differentiation in embryonic stem cells, its specific role in iPS cells remains unclear. To evaluate the function of hMAGEA2 and its characteristics in iPS cells, we produced hMAGEA2-overexpressing iPS cells from hMAGEA2-overexpressing transgenic mice. Although the iPS cells with overexpressed hMAGEA2 did not differ in morphology, their pluripotency, and self-renewal related genes (Nanog, Oct3/4, Sox2, and Stat3), expression level was significantly upregulated. Moreover, hMAGEA2 contributed to the promotion of cell cycle progression, thereby accelerating cell proliferation. Through embryoid body formation in vitro and teratoma formation in vivo, we demonstrated that hMAGEA2 critically decreases the differentiation ability of iPS cells. These data indicate that hMAGEA2 intensifies the self-renewal, pluripotency, and degree of proliferation of iPS cells, while significantly repressing their differentiation efficiency. Therefore, our findings prove that hMAGEA2 plays key roles in iPS cells.

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Reprogramming of prostate cancer‐associated stromal cells to embryonic stem‐like

Abstract: Genes of CP stromal cells could be fully inactivated by genetic reprogramming. As a consequence, the disease phenotype was 'cured'.

Cited by 25 publications

References 37 publications

Cancer-secreted AGR2 induces programmed cell death in normal cells

Cancer-secreted AGR2 induces programmed cell death in normal cells

1322 Lin28 Promotes Growth of Prostate Cancer Cells and Activates the Androgen Receptor

Critical roles of hMAGEA2 in induced pluripotent stem cell pluripotency, proliferation, and differentiation

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