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Cancer-Associated Fibroblasts Support Lung Cancer Stemness through Paracrine IGF-II/IGF1R/Nanog Signaling

ABSTRACT: The CLS1/CAF co-culture maintained the cancer stemness. This cancer stemness was lost when the CAF feeder cells were removed during passaging. To investigate the specific signaling pathways and markers of lung CSCs, we analyzed the gene expression profile of the CLS1 sphere after CLS1/CAF co-culture and compared this profile with that obtained for CLS1 cells cultured without feeder cells through different passages (CLS1 p3, p6, and p14) and CLF1 CLS1 sphere generated by co-culture with CAF and remove CAF to mimic cancer cell differentiation. Four time points of the CLS1 after co-culture with CAF have been collected for microarray analysis:CLS1-2 p.3, p.6, p.8, p.14. We tried to compare theCLS1 sphere-regulated gene expression profiles with the CLS1-2 p.3, p.6, p.8, p.14 and CLF1 to identify the possible cross talk mechanisms of CLF1 and CLS1 and the signaling pathways that maintain stem cell properties.

ORGANISM(S): Homo sapiens

SUBMITTER: Chen WJ

PROVIDER: S-ECPF-GEOD-38678 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Cancer-Associated Fibroblasts Support Lung Cancer Stemness through Paracrine IGF-II/IGF1R/Nanog Signaling

Project description:The CLS1/CAF co-culture maintained the cancer stemness. This cancer stemness was lost when the CAF feeder cells were removed during passaging. To investigate the specific signaling pathways and markers of lung CSCs, we analyzed the gene expression profile of the CLS1 sphere after CLS1/CAF co-culture and compared this profile with that obtained for CLS1 cells cultured without feeder cells through different passages (CLS1 p3, p6, and p14) and CLF1 CLS1 sphere generated by co-culture with CAF and remove CAF to mimic cancer cell differentiation. Four time points of the CLS1 after co-culture with CAF have been collected for microarray analysis:CLS1-2 p.3, p.6, p.8, p.14. We tried to compare theCLS1 sphere-regulated gene expression profiles with the CLS1-2 p.3, p.6, p.8, p.14 and CLF1 to identify the possible cross talk mechanisms of CLF1 and CLS1 and the signaling pathways that maintain stem cell properties.

2014-03-25 | E-GEOD-38678 | biostudies-arrayexpress

Cancer-Associated Fibroblasts Support Lung Cancer Stemness through Paracrine IGF-II/IGF1R/Nanog Signaling

2014-03-25 | GSE38678 | GEO

NANOG modulates stemness in human colorectal cancer.

Project description:NANOG is a stem cell transcription factor that is essential for embryonic development, reprogramming normal adult cells and malignant transformation and progression. The nearly identical retrogene NANOGP8 is expressed in multiple cancers, but generally not in normal tissues and its function is not well defined. Our postulate is that NANOGP8 directly modulates the stemness of individual human colorectal carcinoma (CRC) cells. Stemness was measured in vitro as the spherogenicity of single CRC cells in serum-free medium and the size of the side population (SP) and in vivo as tumorigenicity and experimental metastatic potential in NOD/SCID mice. We found that 80% of clinical liver metastases express a NANOG with 75% of the positive metastases containing NANOGP8 transcripts. In all, 3-62% of single cells within six CRC lines form spheroids in serum-free medium in suspension. NANOGP8 is translated into protein. The relative expression of a NANOG gene increased 8- to 122-fold during spheroid formation, more than the increase in OCT4 or SOX2 transcripts with NANOGP8 the more prevalent family member. Short hairpin RNA (shRNA) to NANOG not only inhibits spherogenicity but also reduces expression of OCT4 and SOX2, the size of the SP and tumor growth in vivo. Inhibition of NANOG gene expression is associated with inhibition of proliferation and decreased phosphorylation of G2-related cell-cycle proteins. Overexpression of NANOGP8 rescues single-cell spherogenicity when NANOG gene expression is inhibited and increases the SP in CRC. Thus, NANOGP8 can substitute for NANOG in directly promoting stemness in CRC.

| S-EPMC3556342 | biostudies-literature

Does reduced IGF-1R signaling in Igf1r+/- mice alter aging?

Project description:Mutations in insulin/IGF-1 signaling pathway have been shown to lead to increased longevity in various invertebrate models. Therefore, the effect of the haplo-insufficiency of the IGF-1 receptor (Igf1r(+/-)) on longevity/aging was evaluated in C57Bl/6 mice using rigorous criteria where lifespan and end-of-life pathology were measured under optimal husbandry conditions using large sample sizes. Igf1r(+/-) mice exhibited reductions in IGF-1 receptor levels and the activation of Akt by IGF-1, with no compensatory increases in serum IGF-1 or tissue IGF-1 mRNA levels, indicating that the Igf1r(+/-) mice show reduced IGF-1 signaling. Aged male, but not female Igf1r(+/-) mice were glucose intolerant, and both genders developed insulin resistance as they aged. Female, but not male Igf1r(+/-) mice survived longer than wild type mice after lethal paraquat and diquat exposure, and female Igf1r(+/-) mice also exhibited less diquat-induced liver damage. However, no significant difference between the lifespans of the male Igf1r(+/-) and wild type mice was observed; and the mean lifespan of the Igf1r(+/-) females was increased only slightly (less than 5%) compared to wild type mice. A comprehensive pathological analysis showed no significant difference in end-of-life pathological lesions between the Igf1r(+/-) and wild type mice. These data show that the Igf1r(+/-) mouse is not a model of increased longevity and delayed aging as predicted by invertebrate models with mutations in the insulin/IGF-1 signaling pathway.

| S-EPMC3223158 | biostudies-literature

Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation

Project description:Growing evidence supports that LKB1-deficient KRAS-driven lung tumor represents a unique therapeutic challenge, displaying strong cancer plasticity which promotes lineage conversion and drug resistance. Here we find that murine lung tumors from KrasLSL-G12D/+; Lkb1flox/flox (KL) model show strong plasticity which links to up-regulation of stem cell pluripotency genes such as Nanog. Deletion of Nanog in KL model initiates gastric differentiation program and promotes mucinous lung tumor growth. We find that NANOG is not expressed at a meaningful level in human lung adenocarcinoma (ADC) as well as human lung invasive mucinous adenocarcinoma (IMA). The gastric differentiation involves the activation of Notch signaling and perturbation of Notch pathway by the ?-secretase inhibitor LY-411575 remarkably impairs mucinous tumor formation. In contrast to non-mucinous tumors, these mucinous tumors are resistant to phenformin treatment. Such therapeutic resistance could be overcome through combined treatments with LY-411575 and phenformin. Overall, we uncover a previously unappreciated plasticity of LKB1-deficient tumors and identify the Nanog-Notch axis in regulating gastric differentiation, which holds important therapeutic implication against mucinous lung cancer.

| S-SCDT-EMM-2020-12627 | biostudies-other

Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation.

Project description: Not available

| S-EPMC8422069 | biostudies-literature

Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation.

Project description:Growing evidence supports that LKB1-deficient KRAS-driven lung tumors represent a unique therapeutic challenge, displaying strong cancer plasticity that promotes lineage conversion and drug resistance. Here we find that murine lung tumors from the KrasLSL-G12D/+ ; Lkb1flox/flox (KL) model show strong plasticity, which associates with up-regulation of stem cell pluripotency genes such as Nanog. Deletion of Nanog in KL model initiates a gastric differentiation program and promotes mucinous lung tumor growth. We find that NANOG is not expressed at a meaningful level in human lung adenocarcinoma (ADC), as well as in human lung invasive mucinous adenocarcinoma (IMA). Gastric differentiation involves activation of Notch signaling, and perturbation of Notch pathway by the γ-secretase inhibitor LY-411575 remarkably impairs mucinous tumor formation. In contrast to non-mucinous tumors, mucinous tumors are resistant to phenformin treatment. Such therapeutic resistance could be overcome through combined treatments with LY-411575 and phenformin. Overall, we uncover a previously unappreciated plasticity of LKB1-deficient tumors and identify the Nanog-Notch axis in regulating gastric differentiation, which holds important therapeutic implication for the treatment of mucinous lung cancer.

| S-EPMC7933951 | biostudies-literature

Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by its hypovascularity, with an extremely poor prognosis because of its highly invasive nature. PDAC proliferates with abundant stromal cells, suggesting that its invasive activity might be controlled by intercellular interactions between cancer cells and fibroblasts. Using four PDAC cell lines and two pancreas cancer-associated fibroblasts (CAFs), the expression of insulin-like growth factor-1 (IGF1) and IGF1 receptor (IGF1R) was evaluated by RT-PCR, FACScan, western blot, or ELISA. Correlation between IGF1R and the hypoxia marker carbonic anhydrase 9 (CA9) was examined by immunohistochemical staining of 120 pancreatic specimens. The effects of CAFs, IGF1, and IGF1R inhibitors on the motility of cancer cells were examined by wound-healing assay or invasion assay under normoxia (20% O2) and hypoxia (1% O2). IGF1R expression was significantly higher in RWP-1, MiaPaCa-2, and OCUP-AT cells than in Panc-1 cells. Hypoxia increased the expression level of IGF1R in RWP-1, MiaPaCa-2, and OCUP-AT cells. CA9 expression was correlated with IGF1R expression in pancreatic specimens. CAFs produced IGF1 under hypoxia, but PDAC cells did not. A conditioned medium from CAFs, which expressed αSMA, stimulated the migration and invasion ability of MiaPaCa-2, RWP-1, and OCUP-AT cells. The motility of all PDAC cells was greater under hypoxia than under normoxia. The motility-stimulating ability of CAFs was decreased by IGF1R inhibitors. These findings might suggest that pancreas CAFs stimulate the invasion activity of PDAC cells through paracrine IGF1/IGF1R signaling, especially under hypoxia. Therefore the targeting of IGF1R signaling might represent a promising therapeutic approach in IGF1R-dependent PDAC.

| S-EPMC4972430 | biostudies-literature

The IGF2/IGF1R/Nanog Signaling Pathway Regulates the Proliferation of Acute Myeloid Leukemia Stem Cells.

Project description:Acute myeloid leukemia is an aggressive disease characterized by clonal proliferation and differentiation into immature hematopoietic cells of dysfunctional myeloid precursors. Accumulating evidence shows that CD34+CD38- leukemia stem cells (LSCs) are responsible for drug resistance, metastasis, and relapse of leukemia. In this study, we found that Nanog, a transcription factor in stem cells, is significantly overexpressed in CD34+ populations from patients with acute myeloid leukemia and in LSCs from leukemia cell lines. Our data demonstrate that the knockdown of Nanog inhibited proliferation and induced cell cycle arrest and cell apoptosis. Moreover, Nanog silencing suppressed the leukemogenesis of LSCs in mice. In addition, we found that these functions of Nanog were regulated by the insulin-like growth factor receptor (IGF1R) signaling pathway. Nanog overexpression rescued the colony formation ability of LSCs treated with picropodophyllin (PPP), an IGF1R inhibitor. By contrast, knockdown of Nanog abolished the effects of IGF2 on the colony formation ability of these LSCs. These findings suggest that the IGF2/IGF1R/Nanog signaling pathway plays a critical role in LSC proliferation.

| S-EPMC6036281 | biostudies-literature

The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance.

Project description:Insulin-like Growth Factor (IGF)/IGF-1 Receptor (IGF-1R) signaling is known to regulate stem cell pluripotency and differentiation to trigger cell proliferation, organ development, and tissue regeneration during embryonic development. Unbalanced IGF/IGF-1R signaling can promote cancer cell proliferation and activate cancer reprogramming in tumor tissues, especially in the liver. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, with a high incidence and mortality rate in Asia. Most patients with advanced HCC develop tyrosine kinase inhibitor (TKI)-refractoriness after receiving TKI treatment. Dysregulation of IGF/IGF-1R signaling in HCC may activate expression of cancer stemness that leads to TKI refractoriness and tumor recurrence. In this review, we summarize the evidence for dysregulated IGF/IGF-1R signaling especially in hepatitis B virus (HBV)-associated HCC. The regulation of cancer stemness expression and drug resistance will be highlighted. Current clinical treatments and potential therapies targeting IGF/IGF-1R signaling for the treatment of HCC will be discussed.

| S-EPMC7919800 | biostudies-literature

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