Cancer-associated fibroblasts (CAFs) secrete various pro-tumorigenic cytokines, yet the role of these cytokines in the progression of endometrial cancer remains unclear. We found that CAFs isolated from human endometrial cancer (EC) tissues secreted high levels of interleukin-6 (IL-6), which promotes EC cell proliferation in vitro. Neutralizing IL-6 in CAF-conditioned media reduced (47% inhibition) while IL-6 recombinant protein increased cell proliferation (~2.4 fold) of both EC cell lines and primary cultures. IL-6 receptors (IL-6R and gp130) were expressed only in EC epithelial cells but not in CAF, indicating a one-way paracrine signaling. In the presence of CAF-conditioned media, Janus kinase/signal transducers and activators of transcription (JAK/STAT3) pathway was activated in EC cells. Treatment with JAK and STAT3 specific inhibitors, AD412 and STATTIC, respectively, significantly abrogated CAF-mediated cell proliferation, indicating the role of IL-6 activation in EC cell proliferation. We further showed that one of STAT-3 target genes, c-Myc, was highly induced in EC cells after exposure to CAF-conditioned medium at both mRNA (>105-fold vs. control) and protein level (>2-fold vs. control). EC cell proliferation was dependent on c-Myc expression, as RNAi-mediated c-Myc down-regulation led to a significant 46% reduction in cell viability when compared with scrambled control. Interestingly, CAF-conditioned media failed to promote proliferation in EC cells with reduced c-Myc expression, suggesting that CAF-mediated cell proliferation was also dependent on c-Myc expression. Subcutaneous tumor xenograft model showed that EC cells grew at least 1.4 times larger when co-injected with CAF, when compared to those injected with EC cells alone. Mice injected with EC cells with down-regulated c-Myc expression, however, showed at least 2.5 times smaller tumor compared to those in control group. Notably, there was no increase of tumor size when co-injected with CAFs. Further immunohistochemical staining on human tissues showed positive expression of IL-6 receptors, phosphorylated-STAT3 and c-Myc in human EC tissues with less signals in benign endometrium. Taken together, our data suggests that IL-6 secreted by CAF induces c-Myc expression to promote EC proliferation in vitro and in vivo. IL-6 pathway can be a potential target to disrupt tumor-stroma interaction in endometrial cancer progression.
The mammalian DREAM (Drosophila, RB, E2F, and Myb) complex was discovered in 2004 by several research groups. It was initially identified in Drosophila followed by Caenorhaditis elegans and later in mammalian cells. The composition of DREAM is temporally regulated during cell cycle; being associated with E2F-4 and either p107 or p130 in G0/G1 (repressive DREAM complexes) and with B-myb transcription factor in S/G2 (activator DREAM complex). High risk human papillomavirus (HPV) E6 and E7 oncoproteins expression are important for malignant transformation of cervical cancer cells. In particular, the E7 of high risk HPV binds to pRB family members (pRB, p107 and p130) for degradation. It has recently been discovered that the p107 and p130 'pocket proteins' are members of mammalian DREAM complexes. With this understanding, we would like to hypothesise the mammalian DREAM complex could plays a critical role for malignant transformation in cervical cancer cells.
Breast cancer is one of the most common malignancies among women worldwide, and metastasis remains the leading cause of breast cancer-related mortality. Although PLXNB2 regulates cell migration and intracellular signaling, its expression pattern and mechanistic role in breast cancer progression and lung metastasis remain unclear. This study investigated PLXNB2 expression in breast cancer (BRCA) and examined its contribution to tumor progression and pulmonary metastasis. PLXNB2 expression in tumor and adjacent normal tissues was analyzed using The Cancer Genome Atlas (TCGA) data. Weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, single-cell transcriptomics, and spatial transcriptomics were used to identify PLXNB2-associated pathways and cellular contexts. Associations with tumor grade and survival were evaluated in clinical cohorts, and the effects of lentiviral PLXNB2 knockdown on proliferation, migration, and invasion were assessed in breast cancer cell lines. Tumorigenicity and metastasis were further examined in vivo. PLXNB2 was significantly upregulated in breast cancer and was enriched predominantly in malignant epithelial cells. High PLXNB2 expression independently predicted poor overall survival in the GSE20711 cohort (HR = 1.610; 95% CI, 1.100-2.357; P = 0.013) and was positively associated with tumor grade (P < 0.05). WGCNA and transcriptomic analyses identified AMPK signaling as a key downstream pathway. PLXNB2 knockdown reduced p-AMPK and p-ACC1 levels without altering total AMPK or ACC1 expression, and reciprocal endogenous co-immunoprecipitation detected AMPK in PLXNB2 immunoprecipitates and PLXNB2 in AMPK immunoprecipitates, supporting an association between the two proteins. In vivo, PLXNB2 depletion reduced tumor growth, lung metastasis, and p-AMPK and p-ACC1 expression. These findings indicate that PLXNB2 promotes breast cancer progression and lung metastasis by activating AMPK signaling and may serve as a diagnostic, prognostic, and therapeutic biomarker.
Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive subtype of extranodal diffuse large B-cell lymphoma. It is characterized by the selective proliferation of lymphoma cells within the lumina of small blood vessels. Collision tumors involving IVLBCL are exceedingly rare, and no cases involving paraganglioma as a collision component have been reported to date. We report the case of an 80-year-old man who presented with nonspecific gastrointestinal symptoms and intermittent fever. Imaging studies suggested biliary and intra-abdominal malignancies. Surgical resection revealed a mesenteric mass. Histopathological examination demonstrated features consistent with paraganglioma. Notably, numerous atypical lymphoid cells were identified within the lumina of small vessels in the tumor. Immunohistochemical analysis showed positivity for CD20, CD19, PAX5, MUM1, and BCL2, supporting a diagnosis of IVLBCL. Epstein-Barr virus-encoded RNA (EBER) in situ hybridization was negative. Systemic involvement was excluded based on clinical evaluation and imaging findings. The final diagnosis was IVLBCL in collision with paraganglioma. Given the patient's advanced age and poor performance status, intensive chemotherapy was considered unsuitable, and targeted therapy with 'Surufatinib' was initiated. During follow-up, no recurrence of the primary tumor was observed. However, the patient subsequently developed duodenal adenocarcinoma and received appropriate treatment. The patient died approximately two years after the initial diagnosis. To the best of our knowledge, based on a systematic literature search in PubMed up to April 2026, this is the first reported case of a collision tumor composed of paraganglioma and IVLBCL. This case underscores the diagnostic challenges of IVLBCL due to its nonspecific presentation and its potential to be overlooked when coexisting with other tumors. Careful histopathological evaluation, particularly of intravascular components, is essential for accurate diagnosis. Increased awareness may facilitate early detection and improve patient outcomes.