bims-meluca 2020-08-30 papers

Cancers (Basel). 2020 Aug 24. pii: E2402. [Epub ahead of print]12(9):

Midkine Is a Potential Therapeutic Target of Tumorigenesis, Angiogenesis, and Metastasis in Non-Small Cell Lung Cancer.

Shin DH, Jo JY, Kim SH, Choi M, Han C, Choi BK, Kim SS.

Hypoxia-inducible factors (HIFs) induced by reduced O2 availability activate the transcription of target genes encoding proteins that play important roles in communication between cancer and stromal cells. Cancer cells were incubated under hypoxic conditions: H1299, A549 (NSCLC); Hep3B, HepG2 (HCC); HCT116, CT26 (Colon cancer); MCF-7, MDAMB231 (Breast cancer); MKN1, MKN5 (Gastric cancer); U87MG, SHSY5Y (Brain cancer); and SKOV3, SNU840 (Ovary cancer). All cells expressed HIF-1α and HIF-2α mRNA and proteins. However, cell proliferation of NSCLC, breast, gastric, and brain cancer cells under hypoxia was more dependent on HIF-1α except for HCC cells where it was more dependent on HIF-2α. Among HIF-1α dependent cells H1299 was the most affected in terms of cell proliferation by HIF-1α knockdown. To examine which cytokines are secreted in NSCLC cells by HIF-1α to communicate with stromal cells, we performed a cytokine-profiling array with H1299. We screened the top 14 cytokines which were dependent on the HIF-1α expression pattern. Among them, midkine (MDK) expression was affected the most in response to HIF-1α. MDK is a heparin-binding growth factor that promotes angiogenesis and carcinogenesis. Indeed, MDK significantly increased HUVEV endothelial cell migration and neo- vascularization in chick chorioallantoic membrane assay (CAM) assay via paracrine signaling. In addition, MDK secreted from NSCLC cells interacted with Notch2 which activated the Notch signaling pathway and induced EMT, upregulated NF-κB, and increased cancer promotion. However, in response to MDK knock down, siRNA or the MDK inhibitor, iMDK treatment not only decreased MDK-induced migration and angiogenesis of endothelial cells but also abrogated the progression and metastasis of NSCLC cells in in vitro and in vivo orthotopic and spontaneous lung metastasis models. Consequently, iMDK treatment significantly increased mice survival rates compared with the control or MDK expression group. MDK plays a very important role in the progression and metastasis of NSCLC cells. Moreover, the MDK targeting strategy provides a potential therapeutic target for the treatment of MDK-expressing lung cancers.

Keywords: NSCLC; angiogenesi; metastasis; midkine; tumor progression

DOI: https://doi.org/10.3390/cancers12092402

Cancer Sci. 2020 Aug 28.

Chaperon-Mediated Autophagy Receptor Modulates Tumor Growth and Chemoresistance in Non-Small Cell Lung Cancer.

Ichikawa A, Fujita Y, Hosaka Y, Kadota T, Ito A, Yagishita S, Watanabe N, Fujimoto S, Kawamoto H, Saito N, Yoshida M, Hashimoto M, Minagawa S, Hara H, Motoi N, Yamamoto Y, Ochiya T, Araya J, Kuwano K.

Chaperone-mediated autophagy (CMA) is a lysosomal degradation pathway of selective soluble proteins. LAMP2A is the key receptor protein of CMA, downregulation of LAMP2A leads to CMA blockade. Although CMA activation has been involved in cancer growth, CMA status and functions in non-small cell lung cancer (NSCLC) by focusing on the roles in regulating chemosensitivity remain to be clarified. In this study, we found that elevated expression of LAMP2A is found in NSCLC cell lines as well as patient's tumors, and confers poor survival and platinum-resistance in NSCLC patients. LAMP2A knockdown in NSCLC cells suppressed cell proliferation and colony formation, and increased the sensitivity to chemotherapeutic drugs in vitro. Furthermore, we found that intrinsic apoptosis signaling is the mechanism of cell death involved with CMA blockade. Remarkably, LAMP2A knockdown repressed tumorigenicity and sensitized the tumors to cisplatin treatment in NSCLC-bearing mice. Our discoveries suggest that LAMP2A is involved in the regulation of cancer malignant phenotypes and represents a promising new target against chemoresistant NSCLC.

Keywords: Apoptosis; Chaperone-mediated autophagy; Chemoresistance; LAMP2A; Lung cancer

DOI: https://doi.org/10.1111/cas.14629

Nucl Med Mol Imaging. 2020 Aug;54(4): 175-182

Relationship of EGFR Mutation to Glucose Metabolic Activity and Asphericity of Metabolic Tumor Volume in Lung Adenocarcinoma.

Whi W, Ha S, Bae S, Choi H, Paeng JC, Cheon GJ, Kang KW, Lee DS.

Purpose: EGFR-mutation (EGFR-mt) is a major oncogenic driver mutation in lung adenocarcinoma (ADC) and is more often observed in Asian population. In lung ADC, some radiomics parameters of FDG PET have been reported to be associated with EGFR-mt. Here, the associations between EGFR-mt and PET parameters, particularly asphericity (ASP), were evaluated in Asian population.Methods: Lung ADC patients who underwent curative surgical resection as the first treatment were retrospectively enrolled. EGFR mutation was defined as exon 19 deletion and exon 21 point mutation and was evaluated using surgical specimens. On FDG PET, image parameters of maximal standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and ASP were obtained. The parameters were compared between EGFR-mt and wild type (EGFR-wt) groups, and the relationships between these PET parameters and EGFR-mt were evaluated.
Results: A total of 64 patients (median age 66 years, M:F = 34:30) were included in the analysis, and 29 (45%) patients showed EGFR-mt. In EGFR-mt group, all the image parameters of SUVmax, MTV, TLG, and ASP were significantly lower than in EGFR-wt group (all adjusted P < 0.050). In univariable logistic regression, SUVmax (P = 0.003) and ASP (P = 0.010) were significant determinants for EGFR-mt, whereas MTV was not (P = 0.690). Multivariate analysis revealed that SUVmax and ASP are independent determinants for EGFR-mt, regardless of inclusion of MTV in the analysis (P < 0.05).
Conclusion: In Asian NSCLC/ADC patients, SUVmax, MTV, and ASP on FDG PET are significantly related to EGFR mutation status. Particularly, low SUVmax and ASP are independent determinants for EGFR-mt.

Keywords: Asphericity; EGFR mutation; FDG PET/CT; Lung cancer; Radiogenomics

DOI: https://doi.org/10.1007/s13139-020-00646-7

Front Oncol. 2020 ;10 1090

Comparison of Metabolic and Morphological Response Criteria for Early Prediction of Response and Survival in NSCLC Patients Treated With Anti-PD-1/PD-L1.

Castello A, Rossi S, Toschi L, Lopci E.

Introduction/Aim: Immunotherapy with immune checkpoint inhibitors (ICIs) has positively changed the history of several malignant tumors. In parallel, new challenges have emerged in the evaluation of treatment response as a result of their peculiar anticancer effect. In the current study, we aimed to compare different response criteria, both morphological and metabolic, for assessing response and outcome in patients with advanced non-small cell lung cancer (NSCLC) treated with ICI. Materials and Methods: Overall, 52 patients with advanced NSCLC candidate to ICI were prospectively evaluated. Inclusion criteria comprised whole-body contrast-enhanced CT and 18F-FDG PET/CT at baseline and at the first response evaluation 3 or 4 cycles after ICI. Response assessment on CT was performed according to RECIST 1.1 and imRECIST criteria, whereas metabolic response on PET was computed by EORTC, PERCIST, imPERCIST, and PERCIMT criteria. The concordance between the different tumor response criteria and the performance of each criterion to predict progression-free survival (PFS) and overall survival (OS) were calculated. Results: Inclusion criteria were fulfilled in 35 out of 52 patients. We observed a low agreement between imRECIST and imPERCIST (κ = 0.143) with discordant response in 20 patients, particularly regarding stable disease and progressive disease groups. Fair agreement between imRECIST and EORTC (κ = 0.340), and PERCIST (κ = 0.342), and moderate for PERCIMT (κ = 0.413) were detected. All criteria were significantly associated with PFS, while only PERCIMT and imPERCIST were associated with OS. Of note, in patients classified as immune stable disease (iSD), imPERCIST, and PERCIMT well-differentiated those with longer PFS (p < 0.001, p = 0.009) and OS (p = 0.001, p = 0.002). In the multivariate analysis, performance status [hazard ratio (HR) = 0.278, p = 0.015], imRECIST (HR = 3.799, p = 0.026), and imPERCIST (HR = 4.064, p = 0.014) were predictive factors for PFS, while only performance status (HR = 0.327, p = 0.035) and imPERCIST (HR = 3.247, p = 0.007) were predictive for OS. Conclusions: At the first evaluation during treatment with ICI, imPERCIST criteria correctly evaluated treatment response and appeared able to predict survival. Moreover, in patients with iSD on CT, imPERCIST were able to discriminate those with longer survival. This advantage might allow for earlier therapy modification based on metabolic response.

Keywords: 18F-FDG PET/CT; EORTC; PERCIMT; PERCIST; RECIST; checkpoint inhibitors; imPERCIST; non-small cell lung cancer

DOI: https://doi.org/10.3389/fonc.2020.01090