Cancer Science最新文献

Ovarian carcinosarcoma (OCS) is a rare and aggressive tumor, and the development of its sarcomatous component is believed to be due to epithelial-mesenchymal transition (EMT). The SWIch/sucrose nonfermentable chromatin remodeling factor (CRF) is closely related to EMT; however, the relationship between CRF and EMT in OCS remains unclear. In this study, we analyzed the protein expression of CRFs, including ARID1A and SMARCA4, and their downstream mRNA expression in 28 OCS cases, two fallopian tube CS cases, and one peritoneal CS case. ARID1A and SMARCA4 exhibited a histological type-specific loss of protein expression in 5 of 11 (45%) endometrioid cases and all 5 serous/homologous OCS cases, respectively. The mRNA analysis suggested that sarcomatogenesis is induced by the transforming growth factor-β and Hippo signaling pathways, both of which regulate YAP1. Immunostaining for YAP1 suggested YAP1-associated sarcomatogenesis in the CRF-retained group, whereas YAP1-unassociated sarcomatogenesis was suggested in the CRF-reduced group. High-grade serous carcinoma cell line experiments showed that the transcriptome of the SMARCA4-knockdown group showed lower expression of the epithelial gene CDH1 and higher expression of mesenchymal genes such as VIM, ZEB1, and SNAI1 than the control group. Moreover, cell adhesion disappeared and cell morphology changed to a spindle shape, indicating sarcomatogenesis. In conclusion, this study reveals a mechanism for sarcoma development in OCS and provides novel therapeutic possibilities.

Melanoma-associated antigen (MAGE)-A4, a cancer testis antigen, presents a promising target for chimeric antigen receptor T cell therapy in refractory solid tumors, including breast cancer (BC). However, the lack of highly specific Abs against MAGE-A4 is a major challenge for the development of MAGE-A4-targeted immunotherapies. This study aimed to validate the specificity of a novel MAGE-A4 Ab (E701U) and examine MAGE-A4 expression in clinical BC samples. MAGE-A1, -A2B, -A3, -A4, -A6, -A9, -A10, and -A12 genes were transfected into HEK293 cells. MAGE-A4 expression in each inserted cell block was evaluated using an E701U Ab. Subsequently, we evaluated MAGE-A4 expression in 403 primary BC tissue samples by immunohistochemistry using E701U and analyzed the clinical impact of MAGE-A4 in patients with early BC. The results showed that MAGE-A4 expression was limited to cells transduced with the MAGE-A4 gene. MAGE-A4 expression was observed in 5.7% of the BC samples. Positivity in triple-negative BC was significantly higher than in the other subtypes. The 5-year overall survival rate of patients with MAGE-A4(+) was significantly worse than those with MAGE-A4(-) BC. Moreover, the 5-year recurrence-free survival (RFS) rate of patients with MAGE-A4(+) BC was significantly lower than that of patients with MAGE-A4(-) BC. MAGE-A4 expression was an independent prognostic factor for RFS. In conclusion, the E701U Ab showed reliable specificity for MAGE-A4 expression among MAGE family genes. Patients with MAGE-A4(+) BC have an unfavorable prognosis and represent potential candidates for MAGE-A4-specific immunotherapy.

The depth of invasion plays a critical role in predicting the prognosis of early esophageal cancer, but the reasons behind invasion and the changes occurring in invasive areas are still not well understood. This study aimed to explore the morphological differences between invasive and non-invasive areas in early esophageal cancer specimens that have undergone endoscopic submucosal dissection (ESD), using artificial intelligence (AI) to shed light on the underlying mechanisms. In this study, data from 75 patients with esophageal squamous cell carcinoma (ESCC) were analyzed and endoscopic assessments were conducted to determine submucosal (SM) invasion. An AI model, specifically a Clustering-constrained Attention Multiple Instance Learning model (CLAM), was developed to predict the depth of cancer by training on surface histological images taken from both invasive and non-invasive regions. The AI model highlighted specific image portions, or patches, which were further examined to identify morphological differences between the two types of areas. The 256-pixel AI model demonstrated an average area under the receiver operating characteristic curve (AUC) value of 0.869 and an accuracy (ACC) of 0.788. The analysis of the AI-identified patches revealed that regions with invasion (SM) exhibited greater vascularity compared with non-invasive regions (epithelial). The invasive patches were characterized by a significant increase in the number and size of blood vessels, as well as a higher count of red blood cells (all with p-values <0.001). In conclusion, this study demonstrated that AI could identify critical differences in surface histopathology between non-invasive and invasive regions, particularly highlighting a higher number and larger size of blood vessels in invasive areas.

The tumor microenvironment is composed of tumor cells and various stromal cell types, such as immune cells, fibroblasts, and vascular cells. Signaling interactions between tumor and stromal cells orchestrate the tumor microenvironment's contribution to tumor progression. Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein homologous to angiopoietins. Previous studies indicate that tumor cell-derived ANGPTL2 serves as a tumor promoter. However, recent studies suggest that tumor stroma-derived ANGPTL2 shows tumor-suppressive activity by enhancing anti-tumor immune responses, supporting a dual function for ANGPTL2 in cancer pathology. Such complexity can complicate development of effective therapeutic strategies targeting ANGPTL2. In this Review, we focus on ANGPTL2 activity in the tumor microenvironment and its function in anti-cancer immunity.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), especially third-generation TKIs, have significantly improved the progression-free survival and overall survival of non-small cell lung cancer (NSCLC) patients with EGFR mutation, TKI resistance is inevitable for most patients. Over the past few years, immune checkpoint inhibitors (ICIs) have significantly improved the survival for EGFR-wild type NSCLC patients. However, no significantly improved benefits were observed with ICI monotherapy in EGFR-mutated patients. EGFR-mutated NSCLC shows more heterogeneity in tumor mutational burden (TMB), programmed cell death-ligand 1 (PD-L1), and immune microenvironment characteristics. Whether ICIs are suitable for EGFR-mutated NSCLC patients remains to be elucidated. In this review, we summarized clinical trials of ICIs or combined therapy in EGFR-mutated NSCLC patients. We further discussed the factors determining the efficacy of ICIs in EGFR-mutated NSCLC patients, the mutation subtypes and microenvironment characteristics of potential responders. More importantly, we provided insights into areas worth further investigation in the future.

Near-infrared photoimmunotherapy (NIR-PIT) is a novel antitumor therapy that selectively kills cancer cells by NIR light-triggered photochemical reaction of IRDye700DX within Ab-photoabsorber conjugates (APCs). NIR-PIT induces immunogenic cell death, causing immune cell migration between the tumor and tumor-draining lymph nodes, and expanding multiclonal tumor-infiltrating CD8⁺ T cells. Crucially, the cytotoxic effects of NIR-PIT are limited to cancer cells, sparing immune cells such as antigen-presenting cells and T cells, which are key players in boosting antitumor host immunity. By modifying the Ab used in APC synthesis, NIR-PIT can be repurposed to target and deplete noncancerous immunosuppressive cells including regulatory T cells, myeloid-derived suppressor cells, and cancer-associated fibroblasts in the tumor microenvironment. Immunosuppressive cell targeted NIR-PIT strongly potentiates antitumor host immunity, including the induction of abscopal effects and the development of immune memory. Furthermore, antitumor immune responses and therapeutic efficacy are synergistically enhanced when NIR-PIT is combined with other immune-activating treatments, such as interleukin-15 and immune checkpoint inhibitors. These new findings make NIR-PIT a valuable tool in the evolving landscape of cancer immunotherapy. This review explains the role of NIR-PIT in activating antitumor host immunity.

Personalized radiotherapy based on the intrinsic sensitivity of individual tumors is anticipated, however, it has yet to be realized. To explore cancer radiosensitivity, analysis in combination with omics data is important. The Cancer Cell Line Encyclopedia (CCLE) provides multi-layer omics data for hundreds of cancer cell lines. However, the radiosensitivity counterpart is lacking. To address this issue, we aimed to establish a database of radiosensitivity, as assessed by the gold standard clonogenic assays, for the CCLE cell lines by collecting data from the literature. A deep learning-based screen of 33,284 papers identified 926 relevant studies, from which SF₂ (survival fraction after 2 Gy irradiation) data were extracted. The median SF₂ (mSF₂) was calculated for each cell line, generating an mSF₂ database comprising 285 cell lines from 28 cancer types. The mSF₂ showed a normal distribution among higher and lower cancer-type hierarchies, demonstrating a large variation across and within cancer types. In selected cell lines, mSF₂ correlated significantly with the single-institution SF₂ obtained using standardized experimental protocols or with integral survival, a radiosensitivity index that correlates with clonogenic survival. Notably, the mSF₂ for blood cancer cell lines was significantly lower than that for solid cancer cell lines, which is in line with the empirical knowledge that blood cancers are radiosensitive. Furthermore, the CCLE-derived protein levels of NFE2L2 and SQSTM1, which are involved in antioxidant damage responses that confer radioresistance, correlated significantly with mSF₂. These results suggest the robustness and potential utility of the mSF₂ database, linked to multi-layer omics data, for exploring cancer radiosensitivity.

The abnormal expression of PHAX was observed in esophageal cancer, however, its specific function and mechanism remain to be further elucidated. We demonstrated that PHAX, LIN28B, and PBX3 were upregulated in esophageal cancer, while TET2 was downregulated. Elevated PHAX correlated with adverse outcomes among esophageal cancer patients. PHAX or PBX3 knockdown not only inhibited esophageal cancer cell proliferation, and promoted apoptosis and autophagy in vitro, but it also repressed tumor growth and lung metastasis in mice. Mechanically, PHAX stabilized PBX3 mRNA through interacting with LIN28B. PBX3 directly bound to the TET2 promoter region and inhibited its expression. In conclusion, PHAX directly bound to LIN28B and enhanced LIN28B-mediated stabilization of PBX3 mRNA, leading to upregulation of PBX3. PBX3 then transcriptionally repressed TET2 expression to promote esophageal cancer cell proliferation, and suppress apoptosis and autophagy. Targeting this signaling cascade could represent a promising therapeutic strategy for esophageal cancer.

Cancer-associated fibroblasts (CAFs) are essential players in the tumor microenvironment (TME) due to their roles in facilitating tumor progression and metastasis. It is worth noting that the high-metastatic hepatocellular carcinoma (HCC) cell-derived exosomes have exhibited the ability to transform normal fibroblasts into CAFs, which further fosters the lung metastasis of low-metastatic HCC cells. Yet, the mechanisms underlying this tumor exosome-induced metastatic niche formation are poorly explored. In this study, the secreted protein arginyl aminopeptidase (RNPEP) was highly expressed in the plasma of patients with HCC. In addition, high-metastatic HCC cells showed augmented RNPEP expression levels in their exosomes. These exosomes induced obvious CAF-like properties in the human fibroblast cell line MRC-5, as evidenced by the increased CAF marker expression, and enhanced migratory ability. More strikingly, the secretions from high-metastatic tumor exosome-educated MRC-5 cells increased tumor stemness and promoted epithelial-mesenchymal transition (EMT) in MHCC-97L cells, a low-metastatic HCC cell line. However, the knockdown of RNPEP in exosomes from high-metastatic HCC cells abated the changes described above. Animal studies in vivo highlighted the pro-tumor and pro-metastatic effects of exosomal RNPEP on MHCC-97L cells by inducing CAF activation. Furthermore, tumor-derived exosomal RNPEP induced the activation of NF-κB signaling in MRC-5 cells, a critical pathway associated with CAF activation. Collectively, these results provide novel insight into tumor-derived exosomal RNPEP for its crosstalk with CAFs during HCC lung metastasis.

Immune checkpoint inhibitors combined with chemotherapy have shown promising efficacy in treating gastric or gastroesophageal junction (G/GEJ) adenocarcinoma in the neoadjuvant setting. This phase II trial (NCT05715632) aimed to investigate the efficacy and safety of perioperative camrelizumab plus XELOX in patients with locally advanced G/GEJ adenocarcinoma. Treatment-naive patients with cT3-4aN1-3 M0 resectable locally advanced G/GEJ adenocarcinoma were recruited to receive camrelizumab (200 mg, intravenously) on Day 1 combined with XELOX (oxaliplatin at 130 mg/m² on Day 1 and capecitabine at 1000 mg/m² on Days 1-14) every 3 weeks for four cycles, followed by surgery and adjuvant camrelizumab combined with XELOX every 3 weeks for four cycles. The primary endpoint was the pathological complete response (pCR; ypT0N0) rate. From September 2020 to January 2023, 46 patients were enrolled, and all patients completed neoadjuvant therapy. Among them, 43 underwent D2 resection. In the intention-to-treat population, pCR was achieved in nine patients (19.6%, 95% confidence interval [CI]: 9.9%-34.4%), and the major pathological response was achieved in 25 patients (54.3%, 95% CI: 39.2%-68.8%). The objective response rate was 69.6%, of which 12 patients achieved a complete response and 20 patients achieved a partial response. The 1-year event-free survival and disease-free survival rates were both 93.1%. Treatment-related adverse events (TRAEs) occurred in 42 (91.3%) patients, and grade 3 TRAEs occurred in nine (19.6%) patients. No grades 4-5 TRAEs were observed. Perioperative camrelizumab combined with XELOX showed promising pathological response with an acceptable safety profile in patients with resectable locally advanced G/GEJ adenocarcinoma.