Cancer Research and Treatment最新文献

Purpose: We previously demonstrated that WNT signaling, a key regulator of epithelial-mesenchymal transition (EMT), promotes malignancy via RIP1 in colorectal cancer (CRC). In this study, we aimed to reveal the novel signaling pathway through which WNT3A induces EMT in CRC.

Materials and methods: CRC cells (DLD-1, HCT116) and mouse embryonic fibroblasts (MEFs; wtMEF and RIP1-/- MEF) were used in this study. Expression levels of GDF-15 and GFRAL were assessed by RT-qPCR, immunoblotting, and ELISA. RIP1 and HIF-1α were silenced using siRNA or shRNA. Cytokine profiling and ELISA were performed to quantify GDF-15 secretion. Migration and invasion assays were conducted in GDF-15-treated cells. Expression of HIF-1α within the pathway was analyzed with RT-qPCR and immunoblotting. In vivo expressions of GDF-15 and GFRAL were detected in human blood and CRC tissue specimens.

Results: WNT3A treatment significantly upregulated both mRNA and protein levels of GDF-15 and GFRAL in CRC cells. Silencing of RIP1 with siRIP1 or shRIP1 decreased the expression and secretion of GDF-15 and GFRAL. Cytokine profiling and ELISA confirmed that RIP1 facilitates GDF-15 secretion. Treatment with GDF-15 led to enhanced cell migration, invasion, and increased EMT marker expression. We also detected increases of GDF-15 in blood specimens and metastatic tissues of CRC patients. Furthermore, HIF-1α was identified as a key transcription factor downstream of RIP1 that regulates GDF-15 expression.

Conclusion: Our findings demonstrate that the novel WNT3A/RIP1/HIF-1α/GDF-15 signaling axis induces EMT, migration, and invasion in CRC. This pathway might represent a potential therapeutic target for limiting metastatic progression in CRC.

Purpose: Advanced/recurrent endometrial cancer (EC) patients has a poor prognosis, with higher recurrence and mortality than early-stage. However, as the real-world disease burden in these patients remains unclear, we aimed to investigate systemic anticancer therapy (SACT) patterns, healthcare resource utilization (HCRU), and costs in advanced/recurrent EC patients.

Materials and methods: This nationwide population-based study used Korean claims data from 2008 to 2022. Adult patients with advanced/recurrent EC who received first-line SACT were included. For advanced EC, first-line SACT was defined as the initial therapy following EC diagnosis, while for recurrent EC it was defined as the initial therapy after recurrence following completion of primary therapy. We analyzed SACT patterns, prognosis, all cause- and EC-related HCRU, and costs.

Results: A total of 2,704 EC patients were included. The most commonly used SACT was platinum-based regimen. From the first to third line, median values of SACT-free interval (18.40, 5.03, and 3.22 months) and time to next treatment (TTNT, 25.43, 9.27 and 6.44 months) showed decreasing trends. All-cause/EC-related HCRU and costs were increased with SACT progression; all-cause inpatient visits and total costs increased from 0.58 to 1.04 times per-patient-per-month (PPPM) and from $1,197.96 to $2,354.37 USD PPPM.

Conclusion: This study demonstrated significant variability in SACT regimen sequence, highlighting the lack of consensus on standard treatment after disease relapse. Shorter TTNT and SACT-free intervals and higher HCRU and costs in later lines indicate worsening prognosis and increasing disease burden. These findings suggest the urgent need for more effective treatments, including new therapeutic agents, to address the unmet clinical needs of advanced/recurrent EC patients.

Purpose: Esophageal squamous cell carcinoma (ESCC) is frequently accompanied by lymph node metastasis (LNM) to the neck, chest, and abdomen. Despite its significance as a key prognostic factor, the genomic trajectory of LNM remains poorly understood. This study aimed to characterize the underlying patterns and genomic characteristics of LNM.

Materials and methods: Whole-exome sequencing and transcriptome sequencing were performed on 45 multiregional samples (10 primary tumors, 10 normal esophageal tissues, and 25 lymph node tumors) from 10 ESCC patients who underwent esophagectomy with three-field lymphadenectomy. The temporal trajectory of metastasis was reconstructed through phylogenetic analysis, leveraging somatic mutations identified in the primary tumor and lymph nodes.

Results: Somatic mutations preceding metastasis included major driver mutations, such as TP53 and KMT2D, and displayed a mutational process associated with alcohol consumption (SBS16), emphasizing its influence on early tumorigenesis. In contrast, post-lymph node metastatic mutations were sporadic. Lymph nodes seeded later acquired mutations at a faster rate, suggesting increased genomic instability. In three of nine patients (33%), nodal skip metastasis (NSM) was observed, including two cases detected exclusively via genomic analysis, highlighting the necessity of phylogenetic assessment to avoid misclassification. Transcriptome analysis revealed activation of epithelial-mesenchymal transition and KRAS signaling pathways in NSM tumors, indicative of poor prognostic outcomes.

Conclusion: Our study provides a molecular understanding of LNM, emphasizes the potential importance of node-skipping patterns in ESCC, and underscores the utility of genomic analysis in elucidating the connection between LNM.

Purpose: We investigated the real-world efficacy of first-line nivolumab plus ipilimumab (NI) and its predictive clinicopathological biomarkers in patients with advanced renal cell carcinoma(aRCC).

Materials and methods: We retrospectively analyzed 466 patients with aRCC who started first-line NI between 2019 and 2023 at 21 Korean tertiary hospitals. The primary outcome was objective response rate (ORR). Secondary outcomes were duration of response (DoR), progression-free survival (PFS), overall survival (OS), and identification of practical clinicopathological biomarkers.

Results: Median age of patients was 65 years, and 77.7% were male. ORR was 44.8% including 5.2% of complete response, and median DoR was 39.8 months. Male sex and lung metastasis were predictive markers of objective response, and achieving complete response was significantly associated with a longer DoR (p=0.03). With a median follow-up duration of 23.7 months, the median PFS and OS were 11.5 and 44.2 months, respectively. Full exposure to four cycles of ipilimumab was significantly associated with better PFS and OS. Durable response could significantly predict better OS, whereas multiple metastatic sites (≥4) and poor IMDC risk were two independent predictors for inferior OS. Among the 50 patients who completed 2 years of NI treatment, continuation of nivolumab beyond 2 years has marginally improved OS (p=0.09).

Conclusion: First-line NI showed comparable and competent efficacy in Korean patients with aRCC. We suggest completing full exposure to ipilimumab and durable response as practical predictors of enriched benefits of NI in our real-world.

Purpose: The aetiology of colorectal cancer (CRC) is attributed to the intrinsic malignant cell transformation and the extrinsic tumor microenvironment (TME). Within the TME, M2-like tumor-associated macrophages (TAMs) play a pivotal role in promoting CRC malignancy. Although the interaction between tumor cells and TAMs has been studied, the mechanism underlying the polarization of M2-like TAMs directed by CRC cells remains unclear.

Materials and methods: Macrophage polarization was analyzed by flow cytometry. Cytokine production was quantified by qPCR. EVs were identified by transmission electron microscopy and western blotting. CRC cell apoptosis and viability were measured by flow cytometry and CCK8 assay, respectively.

Results: The results showed that CRC cells have high expression of HMGCS1, the enzyme responsible for catalyzing the synthesis of HMG-CoA during cholesterol biosynthesis. The increased expression of HMGCS1 resulted in an excess of cholesterol in CRC patients. The excess cholesterol derived from CRC cells was released via extracellular vesicles (EVs) and taken up by surrounding macrophages via the CD36 receptor. Macrophages that took up CRC cell-derived cholesterol showed a preferential polarization towards M2-like TAMs, which produced large amounts of pro-tumor cytokines. The production of these cytokines further accelerated the progression of the surrounding CRC.

Conclusion: Our findings revealed a mutual stimulatory effect between CRC cells and M2-like TAMs. CRC cells with hyper-expressed HMGCS1 facilitated M2-like TAM polarization by releasing cholesterol-rich EVs, and M2-like TAMs in turn promoted CRC malignancy. These findings suggest that inhibiting excessive cholesterol production may be a promising strategy for the treatment of advanced CRC.

Purpose: Prognostic stratification is essential in non-small-cell lung cancer (NSCLC) to guide treatment decisions. While the TNM staging system has evolved to refine the M category based on metastatic burden, it does not account for differences in prognosis based on the specific organ affected. This study evaluates whether incorporating organ-specific metastasis improves prognostic discrimination in stage IV NSCLC.

Materials and methods: We conducted a retrospective cohort study using data from the Korean Central Cancer Registry (2014-2018). Patients with stage IV NSCLC were classified according to the 9th edition TNM classification: M1b (single-organ, single metastasis), M1c1 (multiple metastases within a single organ), and M1c2 (multiple organ metastases). Survival outcomes were compared across groups using Kaplan-Meier analysis and Cox proportional hazards modeling.

Results: Among 3,165 patients, 56.5% had single-organ metastases, while 43.5% had multiple organ metastases. Median overall survival (OS) was longest in M1b (8.0 months), followed by M1c1 (6.0 months), and shortest in M1c2 (5.9 months) (p<0.001). However, survival varied by metastatic organ. Liver, adrenal, and uncommon-site metastases were associated with significantly worse OS, even among M1b patients. Some M1b and M1c1 patients with high-risk organ metastases had worse survival than M1c2 patients, challenging the TNM-defined prognostic hierarchy.

Conclusion: The current TNM M category does not fully capture the prognostic impact of metastatic organ involvement. Incorporating organ-specific metastases into staging and prognostic models could refine risk stratification and improve personalized treatment approaches for stage IV NSCLC.

Purpose: In 2006, the IARC reported that inorganic lead is carcinogenic in animals but with limited evidence in humans. In addition, some studies have reported that exposure to lead increases the risk of lung cancer, but this remains controversial. Therefore, we aimed to assess the risk of developing lung cancer according to blood lead levels in workers with occupational lead exposure.

Materials and methods: A retrospective cohort study of male workers with 2009 blood lead (PbB) concentrations was conducted using nationwide special health examination data (SHED) from 2009 to 2021 and cancer registry data from 1999 to 2020 from the Republic of Korea. Standardized incidence ratios (SIRs) for lung cancer risk at each PbB level were calculated with a five-year wash-out period, adjusting for age, smoking status, duration of exposure, and the number of co-exposures to lung carcinogens.

Results: The study included 26,092 workers with an average follow-up period of 9.98 years. Compared with workers with PbB levels <3.130 µg/dL, the adjusted SIRs for lung cancer risk were 2.95 (95% confidence interval [CI]: 1.47-5.27) and 3.13 (95% CI: 1.82-5.00) for workers with PbB levels of 3.130-4.899 and ≥4.900 µg/dL, respectively, indicating a significant dose-response trend.

Conclusion: This study demonstrates a significant association between lead exposure and an increased risk of lung cancer, highlighting the need for stronger occupational health policies and ongoing monitoring of workers exposed to lead. The observed dose-response relationship underscores the importance of reassessing current occupational safety standards and strengthening measures to reduce lead exposure in the workplace.

Purpose: Exercise can enhance the therapeutic effects of adjuvant medications, improve both physiological and psychological functions, and increase physical fitness among breast cancer patients receiving adjuvant therapy. This systematic review and meta-analysis examined the latest research on the effects of exercise interventions in this population. Furthermore, subgroup analyses were performed based on exercise type, intensity, frequency, duration and Types of adjuvant therapy.

Materials and methods: The PubMed, Embase, CINAHL, and CENTRAL databases were systematically searched from inception to April 2024 to identify randomized controlled trials (RCTs) examining the use of exercise interventions among breast cancer patients receiving adjuvant therapy. The data extracted from the included studies were analyzed via RevMan 5.4.

Results: A total of 34 studies involving 2,696 participants were included, with 1,369 in the intervention group and 1,327 in the control group, and a mean age ranging from 40 to 60 years. Compared to the control group, exercise interventions improved fatigue, muscular strength, cardiorespiratory fitness, inflammation, and quality of life in breast cancer patients (fatigue: SMD=-0.29, 95% CI (-0.50, 0.09), p=0.005; upper limb strength: SMD=0.50, 95% CI (0.33, 0.68), p<0.00001, lower limb strength: SMD=0.37, 95% CI (0.22, 0.52), p<0.0001; cardiorespiratory fitness: SMD =0.51, 95% CI (0.26,0.75), p<0. 0001; inflammation: SMD =-0.36, 95% CI (-0.66, -0.06), p=0.02; quality of life: SMD=0.21, 95% CI (0.11, 0.31), p< 0.0001). Moderate effect sizes were observed for the alleviation of anxiety and depressive symptoms, although these results did not reach statistical significance (depression: SMD=-0.13, 95% CI (-0.28, 0.02), p=0.08; anxiety: SMD=-0.81, 95% CI (-1.65, 0.03), p=0.06). This meta-analysis was registered in Prospero, the international register of systematic reviews, with registration number: CRD42024553589.

Conclusion: Exercise during adjuvant therapy can reduce the side effects of adjuvant medications, improve both physiological and psychological functions, and enhance physical fitness among patients with breast cancer.

Purpose: Nerve injury-induced protein 1 (Ninj1) is associated with inflammation and tumor progression and shows increased expression in various cancers. This study aimed to investigate the role of Ninj1 in colitis-associated colorectal cancer (CRC) by focusing on its interaction with 17β-estradiol (E2).

Materials and methods: Using an azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model of colitis-associated CRC, wild-type (WT) and Ninj1 knockout (KO) male mice were treated with or without E2.

Results: At week 2, Ninj1 KO mice exhibited attenuated colitis symptoms than WT mice following AOM/DSS treatment. E2 administration significantly alleviated these symptoms in both WT and Ninj1 KO mice, with reductions in the disease activity index, colon length shortening, and histopathological damage. The levels of pro-inflammatory mediators were reduced by E2 treatment in both groups, with the Ninj1 KO group showing a more pronounced response. At week 13, tumor development in Ninj1 KO mice was significantly lower than that in WT mice, particularly in the distal colon. E2 treatment inhibited tumor formation in WT mice and had a stronger inhibitory effect on distal colon tumorigenesis in Ninj1 KO mice. Immune cell populations, including the populations of macrophages and T cells, were also modulated by E2 in WT mice; however, these effects were diminished in Ninj1 KO mice.

Conclusion: These findings suggest that Ninj1 plays a role in modulating colitis and CRC progression, with E2 exerting anti-inflammatory and anti-tumorigenic effects that are influenced by Ninj1 status.

Purpose: The epidermal growth factor receptor (EGFR) is a therapeutic target with confirmed clinical efficacy for several cancer types. We aimed to identify EGFR aberrations and their associations with other genomic alterations in patients with metastatic diseases of various cancers.

Materials and methods: We used real-world data from the next-generation sequencing (NGS) of 3,286 patients with metastatic cancer at the Samsung Medical Center. We analyzed the distribution of EGFR amplification, mutation, and fusion, as well as their correlations with microsatellite instability (MSI), tumor mutation burden (TMB), and other gene aberrations.

Results: A total of 3,286 patients were tested using NGS of a panel covering 523 cancer-related genes (TSO500, Illumina) as part of clinical practice between October 2019 and October 2022. Patients with lung cancer and gliomas were not included in the analysis. Of the 3,286 patients, 175 (5.3%) had EGFR amplification, 38 (1.2%) had EGFR mutations, and eight (0.2%) had EGFR fusion. All 175 patients with EGFR amplifications had microsatellite-stable tumors, but 102 had co-amplifications in other cancer-related genes, and 78 had mutations with clinical significance (tier I/II). Among the 38 patients with EGFR mutations, three (8%) showed MSI-high status, and 11 (29%) demonstrated high TMB (≥ 10 mutations/Mb). Among eight patients with EGFR fusion, three exhibited possible functionalities of the EGFR gene.

Conclusion: EGFR aberrations, mainly amplification, followed by mutation and fusion, were present in 6.4% of patients with metastatic solid tumors.