Oncostatin M orchestrates collective epithelial migration via HIF1A activation.

HIF-1α-associated transcriptional responses to chemical hypoxia in breast and liver cancer cells.

Hypoxia is a defining feature of the tumor microenvironment and a key driver of malignant progression through transcriptional reprogramming of metabolic, angiogenic, and survival pathways. In this study, hypoxia-induced molecular responses were investigated in human hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cells using cobalt(II) chloride (CoCl2) as a hypoxia mimetic. Cell viability profiling was performed to determine the optimal experimental concentration, followed by quantitative PCR analysis of hypoxia-related genes and miRNA-gene interaction network analysis. Cell viability profiling identified 100 µM CoCl2 as the optimal condition for downstream analyses. Quantitative PCR revealed robust induction of HIF-1α in both cell lines, indicating activation of hypoxic signaling. However, downstream responses differed markedly between cell types. MCF-7 cells exhibited significant upregulation of SLC2A1 and increased VEGFA and NFKB1 expression, consistent with activation of glycolytic and pro-angiogenic pathways. In contrast, HepG2 cells showed limited downstream transcriptional engagement despite elevated HIF1A expression. Furthermore, miRNA-gene interaction analysis revealed a dense regulatory network in MCF-7 cells, whereas HepG2 cells displayed a more restricted, VEGFA-centered miRNA profile. These findings demonstrate that chemical hypoxia induces cell-type-specific transcriptional and post-transcriptional responses in breast and liver cancer cells. The results suggest that miRNA-mediated regulation may contribute to differential tumor adaptation to hypoxic stress and highlight the importance of cellular context in hypoxia-associated signaling pathways.

Context-dependent promotion of epithelial-mesenchymal transition by IL-13Rα2/STAT6 signaling in colorectal cancer.

Functional regulation of midkine (MDK) and its link to cancer.

Midkine (MDK) is a heparin-binding growth factor that is minimally expressed in most adult tissues but markedly upregulated in a wide range of malignancies. Accumulating evidence positions MDK as a multifunctional signaling hub that orchestrates tumor progression through its pleiotropic effects on cancer cells and the tumor microenvironment. MDK engages multiple cell surface receptors, including anaplastic lymphoma kinase, low-density lipoprotein receptor-related protein 1, Notch2, and integrins, thereby activating key downstream pathways such as PI3K/AKT, MAPK/ERK, JAK/STAT, and mTOR. Through these signaling networks, MDK promotes tumor cell proliferation, survival, invasion, angiogenesis, metabolic reprogramming, and resistance to therapy. In parallel, MDK exerts profound immunomodulatory effects by shaping the tumor microenvironment, facilitating the recruitment and polarization of immunosuppressive myeloid cells, impairing effector lymphocyte function, and regulating stromal and neural cell interactions via paracrine signaling mechanisms. Recent single-cell transcriptomic studies further highlight MDK's role in mediating intercellular communication across diverse pathological contexts, underscoring its function beyond tumor-intrinsic signaling. Given its extracellular accessibility, disease-associated overexpression, and central role in multiple oncogenic processes, MDK has emerged as an attractive therapeutic target. This review provides a comprehensive overview of the functional regulation of MDK in cancer, summarizing its molecular signaling pathways, contributions to tumor microenvironment remodeling, and involvement in therapeutic resistance. We also discuss current and emerging strategies for targeting MDK, including small-molecule inhibitors, nucleic acid-based approaches, and combination therapies, and highlight key challenges and future directions for translating MDK-targeted interventions into clinical practice.

Rewiring the tumor microenvironment: IGFBP2 at the Nexus of remodeling and therapy resistance?

Insulin-like growth factor binding protein 2 (IGFBP2) has emerged as a multifarious and context-dependent oncoprotein that links several mechanisms in the tumor microenvironment (TME) including oncogenic signaling, extracellular matrix (ECM) remodeling, immune evasion, and therapy resistance. Beyond its established role in modulating IGF signaling, IGFBP2 exerts IGF-independent effects via its RGD integrin-binding motif and nuclear localization signal (NLS). By binding integrins (αvβ3, α5β1), IGFBP2 activates focal adhesion kinase (FAK), which then triggers PI3K/AKT signaling and MAPK/ERK signaling pathways, resulting in enhanced proliferation, migration, invasion, and angiogenesis. Nuclear translocation of IGFBP2, mediated by its NLS, enables direct regulation of gene expression, notably by upregulating epithelial-mesenchymal transition (EMT) transcription factors such as ZEB1, SNAI1, and TWIST1, and regulating immune checkpoint molecules. These actions reshape the TME by increasing angiogenesis, stromal stiffness, and tumor invasiveness. IGFBP2 further sustains survival signals under receptor tyrosine kinase inhibition, enhances tumor cell metabolic adaptation to hypoxia, and supports cancer stemness, all of which drive resistance to chemotherapy, radiotherapy, and immunotherapy. Overexpression of IGFBP2 in cancer is linked to increased tumor aggressiveness, unfavorable prognosis, and general resistance to therapy. Importantly, IGFBP2 functions are highly context-dependent, in some epithelial settings, IGFBP2 sequesters IGFs and dampens IGF-IR signaling, resulting suppression of downstream oncogenic pathways. This duality underscores IGFBP2's nuance and tumor-specific biology. Therapeutic strategies under development specifically target IGFBP2-integrin-mediated signaling and IGFBP2 nuclear activity. There are encouraging results in preclinical studies involving antisense oligonucleotides, monoclonal antibodies, and peptide inhibitors. As both a mediator of oncogenic adaptation and a clinical biomarker, IGFBP2 represents a vulnerability in the TME that may be targeted to improve, personalize, and combine cancer therapies.

The intersection of chemokine signaling with the hallmarks of cancer in glioblastoma

Glioblastoma, IDH-wildtype, is characterized by diffuse invasion, profound immunosuppression, treatment resistance, and near-inevitable recurrence. Although canonical genetic alterations establish malignant capacity, they do not fully explain how glioblastoma cells adapt to hypoxic, perivascular, invasive, immunosuppressive, metabolically constrained, and treatment-injured microenvironments. We examined how chemokine signaling contributes to these adaptive behaviors. We used the hallmarks of cancer as an organizing framework to synthesize preclinical, translational, and clinical evidence on chemokine circuits in glioblastoma. We evaluated recurrent mechanistic pathways, distinguished causal functions from context-dependent biomarker associations, and assessed their therapeutic relevance. Chemokines act primarily as spatial and stress-responsive regulators rather than initiating oncogenic drivers. Recurrent circuits include CXCL12–CXCR4 in vascular repair, invasion, and stem-like persistence; CCL2 and CCL7 signaling through CCR2 in suppressive myeloid recruitment and metabolic–immune remodeling; CCL5–CCR5 in perivascular protection, invasion, and DNA-damage tolerance; and CXCL8 signaling through CXCR1 and CXCR2 in angiogenesis, immune evasion, and therapy-induced plasticity. Most chemokine-directed strategies remain preclinical or early translational. Therapeutic development should prioritize biomarker-defined dependencies and appropriately timed combinations that disrupt selected chemokine-dependent interactions within specific biological and treatment contexts. Clinical translation will require verification of target engagement, disruption of the relevant cellular interactions, and evidence that chemokine modulation improves treatment response or delays recurrence.

Lysyl oxidase drives ccRCC progression by coordinating HIF-2α transcription program with tumor microenvironment

Clear cell renal cell carcinoma (ccRCC) is driven by persistent HIF-2α transcription program initiated by VHL loss, yet molecular mediators sustaining this program are poorly defined. Using single-cell transcriptomics, we identified lysyl oxidase (LOX) as a driver of ccRCC progression, selectively enriched in a hypoxia/epithelial-mesenchymal transition (EMT) gene program associated with poor outcome. While LOX oxidizes and stabilizes HIF-2α by antagonizing HUWE1-mediated ubiquitination and degradation, thereby sustaining HIF-2α-driven transcription in cancer cells, it also remodels extracellular matrix (ECM) and promotes angiogenesis in the tumor microenvironment (TME). Genetic or pharmacological inhibition of LOX destabilizes HIF-2α, disrupts ECM, inhibits angiogenesis, and suppresses tumor initiation, growth, and metastasis in vivo. LOX inhibition enhances anti-angiogenic therapy response and remains effective in belzutifan-resistant HIF-2α G323E-mutant tumors. Nuclear LOX protein correlates with nuclear HIF-2α in high-grade patient tumors. Together, LOX coordinates HIF-2α transcription program with TME and is a therapeutic target in ccRCC.