━━ Objectives. This study verified whether or not high-resolution computed tomography (CT) and fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT are useful for predicting the tumor malignancy grade in lung adenocarcinoma. Materials and Methods. We identified 78 patients with cTis/T1 adenocarcinoma of the lung who underwent FDG-PET/CT at the same hospital and received surgery between April 2016 and February 2021. We classified them into three groups based on the 5 th WHO grade classification. The relationships between the groups and clinicopathological factors, including the consolidation tumor ratio (CTR) and maximum standardized uptake value (SUVmax), were investigated. The cut-off values of the CTR and SUVmax, which predict high-grade malignant tumors, were obtained by a receiver operating characteristic (ROC) analysis, and we combined both values for the evaluation. Results. There were significant differences in the CTR and SUVmax values among the three groups. The rates of lymphovascular invasion and lymph node metastasis were higher in the high-grade group than in the low-grade group. The cut-off values for predicting high-grade malignancy were 97.6% and 3.35 for the CTR and SUVmax, respectively. When the CTR of the tumor was !98% and the SUVmax was >3.35, the sensitivity and specificity for the detection of high-grade lesions were 87.5% and 85.5%, respectively. Conclusion. High-grade malignant cTis/T1 lung adenocarcinoma can be detected by highresolution CT and FGD-PET/CT.
Introduction: Cancer-associated fibroblasts (CAFs) play an important role in cancer progression and malignant transformation by interacting with cancer cells in the tumor microenvironment. Pleural dissemination of non-small cell lung cancer (NSCLC) is a condition in which cancer cells directly spread from the primary tumor site into the extrapulmonary thoracic cavity and colonize the pleura. However, not all free detached cancer cells can survive under anchorage-independent conditions in thoracic cavity, and some important factors are assumed to be involved in the formation of pleural dissemination. In this study, we investigated the role of CAFs in the formation of pleural dissemination in NSCLC. Methods: Using in vitro co-culture models, conditioned medium, and in vivo xenograft models, we investigated CAF-induced phenotypic changes in lung cancer cell: proliferative ability, invasive ability, anchorage-independent growth ability, cell adhesion to extracellular matrix, and tumorigenicity in thoracic cavity. Next, we performed RNA sequencing analysis using 3D co-culture models of cancer cells and CAFs to explore a molecule that contributes to the formation of pleural dissemination, and then verified it using in vitro and in vivo mice models of pleural dissemination. Results: Cancer cells showed enhanced migration, anchorage-independent growth, adhesion, and invasion ability by co-culture with CAFs. In 3D co-culture model of cancer cells and CAFs, even cancer cells which did not form spheroid by themselves acquired the ability of spheroid formation surrounding the CAF core, suggesting that the interactions with CAFs promote spheroid formation. Inoculation of cancer cells together with CAFs into mouse thoracic cavity developed pleural dissemination more efficiently than inoculation of cancer cells alone. RNA sequencing analysis revealed that co-culture with CAFs upregulated the expression of Cellular Communication Network Factor 1 (CCN1), a matricellular protein, in cancer cells. We then verified that ectopically CCN1-overexpressing lung cancer cell lines increased migration and adhesion ability in vitro, and tumorigenicity in thoracic cavity in mouse pleural dissemination model. Conclusions: CAFs promote development of pleural dissemination via driving spheroid formation and upregulating CCN1 expression in NSCLC. Citation Format: Masayoshi Ohki, Naoki Matsuda, Ken Suzawa, Tomohiro Habu, Mao Yoshikawa, Kazuma Iwata, Yin Min Thu, Kazuhiko Shien, Hiromasa Yamamoto, Shinichi Toyooka. Cancer-associated fibroblasts drive spheroid formation and pleural dissemination in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5838.
Background: Cancer-associated fibroblasts (CAFs) are key players in the tumor microenvironment (TME) due to their abundance in most solid tumors and active crosstalk with cancer cells, and promote the initiation of tumor formation, tumor growth, angiogenesis, metastasis, and therapeutic resistance. In this study, we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC). Experimental Design: We established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells using in vitro co-culture models, conditioned medium, and in vivo xenograft mouse models. Next, RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we then verified the biological activity of the identified molecule on NSCLC cells in vitro and in vivo mouse model. Results: Cancer cells showed enhanced cell proliferation, migration, and drug resistance by co-culture with CAFs or CAF-derived conditioned medium. RNA sequencing analysis revealed that CAFs showed higher expressions of POSTN, a matricellular protein, than NFs. Single-cell RNA sequencing data of NSCLC from public database confirmed that POSTN-positive fibroblasts were highly enriched in lung tumor tissues but rarely observed in normal lung tissues, suggesting CAF-specific POSTN expression in lung cancer. Recombinant POSTN increased cell proliferation via NSCLC cells’ ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for Osimertinib treatment. Conclusion: Our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN in TME could be a potential therapeutic strategy for NSCLC. Citation Format: Mao Yoshikawa, Fumiaki Takatsu, Ken Suzawa, Tomohiro Habu, Ohki Masayoshi, Kazuma Iwata, Naoki Matsuda, Yin Min Thu, Kazuhiko Shien, Hiromasa Yamamoto, Shinichi Toyooka. Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5845.
Introduction: The tumor microenvironment (TME) is critical in determining tumor development and progression. Among stromal cells in TME, cancer associated fibroblasts (CAFs) play a central role and are involved in various signals through their interaction with cancer cells in most solid tumors, leading to cancer progression and acquisition of drug resistance. Under these TME conditions, tumor cell death such as necrosis occurs, which in turn, results in the ectopic release of bioactive molecules collectively termed as damage-associated molecular patterns (DAMPs), which has been reported to play an important role in cancer progression. The purpose of this study is to clarify the effects of cancer cell-derived HMGB1, a representative DAMPs, on CAFs and to investigate whether it could be a potential therapeutic target. Methods: We established CAFs from resected non-small cell lung cancer (NSCLC) specimens and investigated the biological activity of HMGB1 on CAFs using in vitro co-culture models with NSCLC cell lines. Furthermore, we assessed the therapeutic efficacy of targeting cancer cell-derived HMGB1 using anti-HMGB1 neutralizing antibody. Results: Intracellular HMGB1 was expressed more in NSCLC cells than in normal bronchial epithelial cells and CAFs, and released from cancer cells extracellularly upon treatment with anticancer drugs. The stimulation with recombinant HMGB1 promoted the proliferation of CAFs in a dose-dependent manner, but not lung cancer cells. Co-culture with CAFs promoted cancer cells’ migratory ability and drug resistance, and stimulation with recombinant HMGB1 further enhanced these promoting effects, while administration of anti-HMGB1 neutralizing antibody suppressed these effects. On the other hand, these inhibitory effects were not observed in the absence of CAFs, suggestingHMGB1 has effect on CAFs, but not direct on cancer cells. Conclusion: HMGB1 plays an important role in cancer progression and acquisition of therapeutic resistance by upregulating the CAFs’ proliferation and activity and could be a therapeutic target in NSCLC. Citation Format: Tomohiro Habu, Keiichi Date, Ken Suzawa, Mao Yoshikawa, Masayoshi Ohki, Kazuma Iwata, Naoki Matsuda, Yin Min Thu, Kazuhiko Shien, Hiromasa Yamamoto, Shinichi Toyooka. The role of high mobility group box-1 protein (HMGB1) in the microenvironment of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2502.
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