Biological determinants of radioresistance and their remediation in pancreatic cancer

Seshacharyulu, Parthasarathy; Baine, Michael J.; Souchek, Joshua J.; Menning, Melanie; Kaur, Sukhwinder; Yan, Ying; Ouellette, Michel; Jain, Maneesh; Lin, Chi; Batra, Surinder K.

doi:10.1016/j.bbcan.2017.02.003

Cited by 88 publications

(67 citation statements)

References 352 publications

(299 reference statements)

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“…Increasing evidence has suggested that cell proliferation, apoptosis, cell cycle progression, and DNA damage are associated with cell radiosensitivity. 24,25 As it was found out, CPNE1 expression levels were higher in radioresistant patients with TNBC than radiosensitive patients with TNBC, and the cell viability was also inhibited significantly in primary isolated TNBC cells with lower CPNE1 expression after radiation therapy. Measurement of γ-H2AX is a sensitive and specific assay for unrepaired DNA damages.…”

Section: Discussionmentioning

confidence: 93%

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

Shao

Zhang³

et al. 2020

Molecular Carcinogenesis

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Elevated expression of Copine 1 (CPNE1) has been observed in multiple cancers; however, the underlying mechanisms by which it affects cancer cells are unclear. We aimed to study the effect of CPNE1 on the tumorigenesis and radioresistance of triple‐negative breast cancer (TNBC). Quantitative real‐time polymerase chain reaction was used to detect the expression of CPNE1 in TNBC tissues and cell lines. Western blot, immunohistochemistry, and immunofluorescence were used to investigate the levels of CPNE1, p‐AKT, AKT, cleaved caspase‐3, cleaved PARP1, and γ‐H2AX. Cell viability and apoptosis were measured by CCK‐8 and flow cytometry, respectively. CPNE1 was overexpressed in TNBC tissues and cell lines and was associated with tumor size, distant metastases, and survival rates of patients with TNBC. Moreover, function study shows that CPNE1 promoted cell viability and inhibited cell apoptosis in vitro and inhibited the radiosensitivity of TNBC. Importantly, inactivation of AKT signaling inhibited the tumorigenesis and radioresistance mediated by CPNE1 in TNBC cells. In vivo xenograft study also shows that CPNE1 knockdown inhibited tumor growth and promoted cell apoptosis. Overall, our findings suggest that CPNE1 promotes tumorigenesis and radioresistance in TNBC by regulating AKT activation and targeted CPNE1 expression may be a strategy to sensitize TNBC cells toward radiation therapy.

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Section: Discussionmentioning

confidence: 93%

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

Shao

Zhang³

et al. 2020

Molecular Carcinogenesis

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“…In fact, only few guidelines and recommendations contain radiotherapy as a standard for primary care of PDA patients 18,19 . In addition to high treatment toxicities, this reluctance is due to intrinsic and acquired radioresistance which is commonly observed both in preclinical and clinical settings 2,20 . Mechanisms associated with the radioresistant phenotype of PDA include modifications in DNA damage response, DNA repair machinery and cell cycle checkpoint controls, as well as the hypoxic environment within the tumour and the activation of stellate cells leading to fibrosis 2 .…”

Section: Discussionmentioning

confidence: 99%

Radiation-induced alterations in immunogenicity of a murine pancreatic ductal adenocarcinoma cell line

Schröter

Hartmann

Osen

et al. 2020

Sci Rep

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Pancreatic ductal adenocarcinoma (PDA) is highlighted by resistance to radiotherapy with the possible exception of hypofractionated irradiation. As single photon doses were reported to increase immunogenicity, we investigated dose-dependent irradiation effects on clonogenic survival, expression of immunologically relevant cell surface molecules and susceptibility to cytotoxic T cell (CTL) mediated killing using a murine PDA cell line. Clonogenicity decreased in a dose-responsive manner showing enhanced radioresistance at single photon doses below 5 Gy. Cell cycle analysis revealed a predominant G2/M arrest, being most pronounced 12 h after irradiation. Polyploidy increased in a dose-and timedependent manner reaching a maximum frequency 60 h following irradiation with 10 Gy. Irradiation increased surface expression of MHC class I molecules and of immunological checkpoint molecules PDL-1 and CD73, especially at doses ≥ 5 Gy, but not of MHC class II molecules and CXCR4 receptors. Cytotoxicity assays revealed increased CTL lysis of PDA cells at doses ≥ 5 Gy. For the PDA cell line investigated, our data show for the first time that single photon doses ≥ 5 Gy effectively inhibit colony formation and induce a G2/M cell cycle arrest. Furthermore, expression levels of immunomodulatory cell surface molecules became altered possibly enhancing the susceptibility of tumour cells to CTL lysis.Despite application of continuously evolving treatment techniques and their individual escalation, prognosis for patients with PDA has remained dismal 1 . The role of radiotherapy in the multimodal treatment approach of PDA has been controversially discussed. In fact, due to its intrinsic properties this tumour entity is generally considered as highly radioresistant and non-immunogenic 2,3 . Recently, several trials have identified hypofractionated photon dose regimens to be associated with increased local control and thus potentially also with survival rates 4-7 . In conventional radiation biology, the use of increased ablative single photon doses commonly overcomes tumour-intrinsic radioresistance by inhibiting repopulation of tumour cells and repair of DNA damage that occur during normofractionated radiotherapy.Several preclinical and clinical trials found increased single photon doses capable of eliciting immunological effects turning irradiated tumours and their stroma into pharmacologically targetable compartments 8 . Regarding PDA, only few preclinical studies have revealed immune stimulatory radiogenic effects so far; the same holds true for studies investigating the clinical benefit of radiotherapy approaches combined with immune checkpoint blockade 9-11 . Currently, there is no consensus about the appropriate photon doses that should be applied in order to induce immunomodulatory alterations in addition to merely anti-proliferative effects. While most of

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“…Distinguishing of molecular mechanisms that diminish the efficacy of radiation therapy and targeting these pathways is important for improving radiation response in patients with pancreatic cancer [183]. In the study of Oonishi and colleagues, the proportion of Nucl Med Biomed Imaging, 2017 doi: 10.15761/NMBI.1000127 cancer stem-like CD44+/CD24+ cells was more enriched after X-ray irradiation compared to carbon ion irradiation.…”

Section: Discussionmentioning

confidence: 99%

The impact of melatonin and carbon ion irradiation on cancer stem cells

Liu¹,

Reíter²

2017

Nucl Med Biomed Imaging

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Aim: Cancer stem cells (CSCs) exhibited an excessive migratory and invasive potential. Melatonin may inhibit multiple crucial signals associated with tumor stem cell self-renewal, viability, invasiveness, tumor growth, and therapy resistance. Carbon ion irradiation may be a promising therapeutic modality in both non-stem-like and stem-like tumor cells in contrast to photon irradiation. A comprehensive understanding of the mechanisms and molecular pathways associated with invasive properties of CSCs is essential in developing novel treatment options for cancer therapy that target CSCs. Materials and methods:A systematic review of the existing literature was conducted using the following search terms: 'melatonin', 'X-ray irradiation', 'charged particle irradiation', 'carbon ion irradiation', 'cancer stem cells', 'tumor-initiating cells' and 'cancer stem-like cells'. The search used PubMed and spanned the period from January 2000 to December 2016. Conclusion:Cancer stem cells possess the capacity of self-renewal and pluripotency, generating all cells within a tumor, and are responsible for tumor growth, therapy resistance and metastasis. Melatonin attenuated AKT activation, EZH2 S21 phosphorylation, EZH2-STAT3 interactions and altered histone modifications to reduce tumor initiation and propagation of brain tumor stem cells (BTSC). Melatonin increases the efficacy of chemotherapeutic agents, targeting both the tumor bulk and BTSCs through the regulation of the expression and function of the ABCG2/BCRP transporter by inducing the methylation of its promoter. Melatonin treatment induced cell death with ultrastructural characteristics of autophagy. Breast cancer stem cells (BCSCs) are responsive to melatonin treatment by way of reducing the viability and the invasiveness of breast cancer mammospheres as well as regulating the expression of OCT4, N-cadherin and vimentin proteins associated with epithelial mesenchymal transition in BCSCs. Carbon irradiation is effective in brain tumor stem cell (BTSC) elimination with relative biologic effectiveness (RBE) in the range of 1.87-3.44. Carbon ion irradiation may be a promising therapeutic modality because it reduces migration and invasion processes in both head and neck squamous cell carcinoma and cancer stem cells in contrast to photon irradiation. Low LET X-ray irradiation may essentially eradicate the non-stem-like tumor cells, consequently the radioresistant cancer stem-like cell population is obviously enriched. In contrast, carbon ion irradiation may eradicate both non-stemlike and stem-like tumor cells at the same time. Carbon ion irradiation is a promising tool to eradicate putative colon cancer stem-like cells. Further investigation to elucidate the mechanisms and molecular pathways involved in cancer stem cells particularly associated with melatonin and carbon ion irradiation certainly is warranted.

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Biological determinants of radioresistance and their remediation in pancreatic cancer

Cited by 88 publications

References 352 publications

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

Radiation-induced alterations in immunogenicity of a murine pancreatic ductal adenocarcinoma cell line

The impact of melatonin and carbon ion irradiation on cancer stem cells

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