Tumor Biology - Volume 44, issue 1

Authors: Ould-Brahim, Fares | Sau, Andrea | Carr, David A. | Jiang, Tianqi | Pratt, M.A. Christine

Article Type: Research Article

Abstract: BACKGROUND: The alternative NF-κ B pathway is activated by the NF-κ B-inducing kinase (NIK) mediated phosphorylation of the inhibitor of κ -B kinase α (IKKα). IKKα then phosphorylates p100/NFKB2 to result in its processing to the active p52 subunit. Evidence suggests that basal breast cancers originate within a subpopulation of luminal progenitor cells which is expanded by signaling to IKKα. OBJECTIVE: To determine the role of IKKα in the development of basal tumors. METHODS: Kinase dead Ikk αAA /AA mice were crossed with the C3(1)-TAg mouse model of basal mammary cancer. Tumor growth …and tumor numbers in WT and Ikk αAA /AA mice were assessed and immunopathology, p52 expression and stem/progenitor 3D colony forming assays were performed. Nik-/- mammary glands were isolated and mammary colonies were characterized. RESULTS: While tumor growth was slower than in WT mice, Ikk αAA /AA tumor numbers and pathology were indistinguishable from WT tumors. Both WT and Ikk αAA /AA tumors expressed p52 except those Ikk αAA /AA tumors where NIK, IKKαAA/AA and ErbB2 were undetectable. Colonies formed by WT and Ikk αAA /AA mammary cells were nearly all luminal/acinar however, colony numbers and sizes derived from Ikk αAA /AA cells were reduced. In contrast to Ikk αAA /AA mice, virgin Nik-/- mammary glands were poorly developed and colonies were primarily derived from undifferentiated bipotent progenitor cells. CONCLUSIONS: C3(1)-TAg induced mammary tumors express p100/p52 even without functional IKKα. Therefore the development of basal-like mammary cancer does not strictly rely on IKKα activation. Signal-induced stabilization of NIK may be sufficient to mediate processing of p100NFKB2 which can then support basal-like mammary tumor formation. Lastly, in contrast to the pregnancy specific role of IKKα in lobuloalveogenesis, NIK is obligatory for normal mammary gland development. Show more

Keywords: Breast tumors, NF-κB, progenitor cells, immunopathology, mammary development

DOI: 10.3233/TUB-220006

Citation: Tumor Biology, vol. 44, no. 1, pp. 187-203, 2022

Authors: Samborski, Alexandra | Miller, M. Craig | Blackman, Alexandra | MacLaughlan-David, Shannon | Jackson, Amanda | Lambert-Messerlian, Geralyn | Rowswell-Turner, Rachel | Moore, Richard G.

Article Type: Research Article

Abstract: BACKGROUND: CA125 is the gold standard serum biomarker for monitoring patients with epithelial ovarian cancer (EOC). Human epididymal protein 4 (HE4) is a novel serum biomarker for EOC patients. OBJECTIVE: The objective of this trial was to examine the utility of measuring serum HE4 levels for monitoring EOC patients and to compare HE4 performance parameters to serum CA125. METHODS: A retrospective trial using residual longitudinal serum samples drawn during treatment and monitoring from EOC patients. Serum CA125 and HE4 levels were analyzed at each time point, and a velocity of change was calculated and correlated with …clinical status. The null hypothesis was that HE4 is inferior to CA125, and this was tested using concordance and two-sided Fisher’s exact testing. McNemar’s test was used to assess the overall agreement of the two assays with the clinical status. RESULTS: A total of 129 patients with 272 separate clinical periods and 1739 events (serum samples) were evaluated. Using a 25% change in serum biomarker levels to indicate change in disease status, the accuracy and NPV determined for HE4 versus CA125 were 81.8% versus 82.6% (p  = 0.846) and 87.4% versus 89.7% (p  = 0.082), respectively. Concordance comparison of HE4 accuracy / CA125 accuracy was 0.990, indicating HE4 was not inferior to CA125 (McNemar’s test p -value = 0.522). Performing a velocity of change analysis, the accuracy and NPV determined for HE4 versus CA125 were 78.3% versus 78.6% (p  = 0.995) and 74.9% versus 76.3% (p  = 0.815), respectively. Concordance comparison of HE4 velocity accuracy / CA125 velocity accuracy was 0.996, again indicating HE4 was not inferior to CA125 (McNemar’s test p -value = 0.884). The combination of HE4 and CA125 velocity changes showed a similar accuracy of 81.3% (p  = 0.797 compared to HE4 and CA125 alone) and NPV of 81.1% (p ≥0.172 compared to HE4 and CA125 alone), and an increased sensitivity of 70.5% (p ≤0.070 compared to HE4 and CA125 alone). CONCLUSION: HE4 is equivalent to CA125 for monitoring of EOC patients. The combination of CA125 and HE4 velocities is superior to either marker alone. Show more

Keywords: Ovarian cancer, biomarkers, CA125, HE4

DOI: 10.3233/TUB-220016

Citation: Tumor Biology, vol. 44, no. 1, pp. 205-213, 2022

Authors: Ghaemi, Zahra | Soltani, Bahram M. | Mowla, Seyed Javad

Article Type: Research Article

Abstract: BACKGROUND: ErbB/PI3K signaling is widely recognized as a critical modulator of malignancy and miRNAs have been found to play a crucial role in the regulation of this pathway. OBJECTIVE: This study aimed to identify novel miRNAs related to the ErbBs loci and investigate the functional effects of these miRNAs on ErbB/PI3K signaling in cancer progression. MATERIALS and METHODS: Bioinformatics tools and RNA-seq data were used to discover novel miRNAs in breast and colon cancer cells. Gene expression levels were determined using RT-qPCR. Western blotting and dual-luciferase assays were used to identify the regulatory mechanism between ErbB4-miR1/2 …and related genes. The effects of ErbB4-miR1/2 on cell proliferation, viability, ROS production, and migration were assessed by PI-flow cytometry, colony formation, MTT, ROS, scratch, and transwell assays in SKBR3 and SW480 cells. RESULTS: MicroRNA prediction tools, RNA-seq data, RT-qPCR, and sequencing results identified ErbB4-miR1 and ErbB4-miR2 (ErbB4-miR1/2) as novel miRNAs encoded by ErbB4 gene. ErbB4-miR1/2 were downregulated in breast and colon tumor tissues and also in different cancerous cells. RT-qPCR and dual-luciferase assays revealed that ErbB2 and ErbB3 genes are regulated by ErbB4-miR1/2. Consistently, a decrease in the p-AKT/AKT protein ratio verified the suppressive effect of ErbB4-miR1/2 on ErbB/PI3K activity. Furthermore, ErbB4-miR1/2 overexpression suppressed cell proliferation, viability, and migration, and increased ROS production. CONCLUSIONS: ErbB4-miR1/2 are novel tumor suppressor miRNAs which attenuate ErbB/PI3K signaling in breast and colon cancer cells. Show more

Keywords: MicroRNA, ErbB/PI3K signaling, ErbB4-miR1/2, tumor suppressor, cancer

DOI: 10.3233/TUB-211570

Citation: Tumor Biology, vol. 44, no. 1, pp. 215-230, 2022

Article Type: Retraction

DOI: 10.3233/TUB-229001

Citation: Tumor Biology, vol. 44, no. 1, pp. 231-231, 2022

Article Type: Retraction

DOI: 10.3233/TUB-229002

Citation: Tumor Biology, vol. 44, no. 1, pp. 233-233, 2022

Article Type: Correction

DOI: 10.3233/TUB-229003

Citation: Tumor Biology, vol. 44, no. 1, pp. 235-235, 2022

Article Type: Correction

DOI: 10.3233/TUB-229004

Citation: Tumor Biology, vol. 44, no. 1, pp. 237-237, 2022

Authors: Tap, William D. | Healey, John H.

Article Type: Research Article

Abstract: Tenosynovial giant cell tumors (TGCTs) are rare, locally aggressive, mesenchymal neoplasms, most often arising from the synovium of joints, bursae, or tendon sheaths. Surgical resection is the first-line treatment, but recurrence is common, with resulting impairments in patients’ mobility and quality of life. Developing and optimizing the role of systemic pharmacologic therapies in TGCT management requires an understanding of the underlying disease mechanisms. The colony-stimulating factor 1 receptor (CSF1R) has emerged as having an important role in the neoplastic processes underlying TGCT. Lesions appear to contain CSF1-expressing neoplastic cells derived from the synovial lining surrounded by non-neoplastic macrophages that express …the CSF1R, with lesion growth stimulated by both autocrine effects causing proliferation of the neoplastic cells themselves and by paracrine effects resulting in recruitment of CSF1 R-bearing macrophages. Other signaling pathways with evidence for involvement in TGCT pathogenesis include programmed death ligand-1, matrix metalloproteinases, and the Casitas B-cell lymphoma family of ubiquitin ligases. While growing understanding of the pathways leading to TGCT has resulted in the development of both regulatory approved and investigational therapies, more detail on underlying disease mechanisms still needs to be elucidated in order to improve the choice of individualized therapies and to enhance treatment outcomes. Show more

Keywords: Tenosynovial giant cell tumor, TGCT, colony-stimulating factor 1, colony-stimulating factor 1 receptor, gene fusion

DOI: 10.3233/TUB-220005

Citation: Tumor Biology, vol. 44, no. 1, pp. 239-248, 2022

Authors: Parekh, Palak R. | Botting, Gregory M. | Thurber, Denise B. | Boruszczak, Marika | Murphy, William | Bertenshaw, Greg P.

Article Type: Research Article

Abstract: BACKGROUND: Non-small cell lung cancer (NSCLC) is a leading cause of cancer deaths. Current companion diagnostics use driver mutation sequencing to select patients for molecularly targeted agents (MTA), even though most patients lack actionable mutations. These diagnostics utilize static biomarkers, ignoring real-time tumor cell biology. OBJECTIVE: Trametinib is FDA-approved in combination with dabrafenib for BRAF V600E-positive NSCLC, however, it has plausible utility beyond these patients. We sought to identify novel biomarkers for maximizing trametinib application. METHODS: Trametinib responses were evaluated in 12 EGFR/BRAF wild-type (WT) NSCLC cell lines with diverse RAS mutational status. …We identified three response categories by colony assay. Trametinib-induced molecular dynamics were studied using immunoassays and apoptosis/necrosis assays, to identify predictive response biomarkers. RESULTS: p27 accumulation and cyclin D1 downregulation suggested universal cell cycle arrest with trametinib. However, 4 cell lines showed PARP cleavage and 8 showed increased phospho-4E-BP1, suggesting varied cellular outcomes from apoptosis, necrosis, senescence to autophagy. Cleaved PARP, phospho-4E-BP1 and phospho-AKT expression can predict these outcomes. CONCLUSIONS: Trametinib monotherapy outcome may depend upon cellular context more than oncogenic mutation status. In BRAF WT NSCLC, trametinib may be best suited for combination therapy and dynamic biomarkers could select combinations and predict responses. Show more

Keywords: Senescence, apoptosis, cell cycle, autophagy, MEK inhibitor

DOI: 10.3233/TUB-220009

Citation: Tumor Biology, vol. 44, no. 1, pp. 249-267, 2022