The clinical backdrop is stark. Breast cancer is the most common malignancy in women, accounting for roughly 16 percent of all female cancers and standing as the leading cause of cancer-related death in this population. Like every solid tumor, a breast tumor cannot exceed a few millimeters in size without solving a supply problem: it must recruit blood vessels that deliver oxygen and nutrients and carry away waste. The canonical solution is angiogenesis, the growth of new capillaries from pre-existing vasculature, orchestrated above all by vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2, which drive endothelial cell proliferation, migration, and survival, while the angiopoietins and their TIE receptors stabilize and mature the emerging network. In the modern formulation of cancer’s hallmarks, inducing and accessing the vasculature is a defining dimension of malignancy, and poor prognosis in breast cancer tracks closely with vascular alterations. Drugs that block the VEGF axis have transformed some areas of oncology, but in breast cancer their benefits have been modest and short-lived, largely because tumors activate vascularization strategies that the drugs never touch.

The most notorious of those strategies is vasculogenic mimicry. First described in highly aggressive melanomas and since reported across carcinomas, it describes the capacity of tumor cells to abandon their epithelial identity, drift toward an endothelial-like phenotype, and remodel the extracellular matrix into fluid-conducting channels that perfuse the tumor independently of normal blood vessels. Molecularly, the adhesion protein VE-cadherin is considered the gatekeeper: it recruits the receptor EphA2 to intercellular junctions, igniting the PI3K and ERK1/2 pathways that sustain tumor cell survival, proliferation, and migration. Matrix metalloproteinases — MMP-2 and MMP-9 in particular — carve these conduits out of the surrounding matrix. Because vasculogenic mimicry flourishes in hypoxic niches and correlates with resistance to anti-angiogenic therapy, identifying the signals that trigger it has become a central question in tumor vascular biology. The result, for patients, is a tumor that supplies itself with oxygen and nutrients while presenting drug developers with a moving target.

Leptin enters the story through the tumor’s own neighborhood. Breast tumors are enveloped in adipose tissue, and the cancer-associated adipocytes that dominate that microenvironment secrete leptin abundantly; the hormone is markedly overexpressed in the tumors of obese patients with estrogen receptor-positive disease. Building on the group’s earlier finding that leptin activates FAK in MCF-7 and MDA-MB-231 breast cancer cells — driving the secretion of MMP-2 and MMP-9, along with migration and invasion — and that the same axis triggers epithelial-to-mesenchymal transition in non-tumorigenic mammary epithelial cells, the team asked a bolder question: does leptin control tumor vascularization itself, and does FAK sit at the center of that control? They hypothesized that leptin regulates both angiogenesis and vasculogenic mimicry through a non-canonical FAK pathway, and assembled a battery of models to find out.

The anchor model was the chick chorioallantoic membrane (CAM), the densely vascularized extraembryonic membrane of fertilized chicken eggs, which allows blood vessel growth to be observed and manipulated directly. Filters soaked with leptin at 50 to 400 nanograms per milliliter were placed on the membrane with or without 5 micromolar PF-573,228, a selective FAK inhibitor, and after five days capillary sprouting, branching, and diameter were quantified morphometrically. In parallel, the researchers implanted 3 million MCF-7 or MDA-MB-231 cells in Matrigel onto the membrane to generate xenograft tumors, treated them with 500 nanograms per milliliter of leptin for 48 hours, and probed the excised tissue by confocal immunofluorescence for VEGF and N-cadherin and by histology for vessel number and caliber. A third arm grew the same cells on Matrigel, stained them with periodic acid-Schiff to expose vasculogenic mimicry structures, and used western blotting to track FAK phosphorylation at tyrosine 397 and a panel of angiogenic proteins. All experiments were performed with independent biological replicates, and only channels with clearly defined lumens were counted as mimicry structures, excluding mere cellular alignment.

On the CAM, leptin behaved as a textbook angiogenic factor, with a twist. Capillary sprouting rose measurably at 50 nanograms per milliliter and peaked at 200, reaching 13.33 sprouts against 2.67 in untreated membranes, while branching climbed dose-dependently from 10.67 to 22.67 branch points compared with a baseline of 5.67. Only the highest dose, 400 nanograms per milliliter, widened the vessels themselves, nearly doubling capillary diameter — evidence of vascular remodeling superimposed on new vessel growth. Low concentrations, in other words, elicit classical sprouting angiogenesis, whereas high concentrations appear to sculpt the existing vasculature, potentially enhancing perfusion, vascular permeability, and the escape of tumor cells into circulation. When FAK was inhibited, the entire program faltered: sprouting collapsed from 13.00 to 3.33 and branching from 18.67 to 6.00 at the 100-nanogram dose, and vessel caliber shrank at every leptin concentration tested. The kinase, the data suggest, is not a helper in leptin-driven angiogenesis but its pivot.

The xenografts revealed that the two breast cancer subtypes read the same hormone differently. Leptin raised VEGF and N-cadherin — an adhesion protein tied to invasion, therapy resistance, and metastasis to the liver, lungs, and lymph nodes — in both MCF-7 and MDA-MB-231 tumors. But the vascular architectures diverged. MCF-7 tumors, of the slower-growing luminal A subtype, responded to leptin with fewer vessels, 13.67 versus 23.50 per section, yet with vessels more than twice as wide, 128.7 versus 59.75 micrometers, a signature of structural remodeling that maintains perfusion without multiplying conduits. Triple-negative MDA-MB-231 tumors did the opposite: leptin increased both vessel density, from 17.50 to 23.33, and diameter, from 31.31 to 54.34 micrometers, in line with the intrinsically proangiogenic character previously documented for triple-negative cells. The luminal tumor rewires its existing network; the triple-negative tumor builds more of it.

Vasculogenic mimicry split along the same fault line. Grown on Matrigel, MCF-7 cells formed defined, lumen-containing tubular channels in a dose-dependent fashion, from 7.67 structures at baseline to 21.00 at the highest leptin dose, and the FAK inhibitor suppressed this tubular mimicry at every concentration tested — clear evidence of FAK dependence in the luminal model. MDA-MB-231 cells instead wove branched, matrix-type patterns into the extracellular matrix, which appeared from 50 nanograms per milliliter onward yet were wholly indifferent to FAK inhibition. Western blotting clarified the molecular underpinnings. In the triple-negative cells, leptin increased FAK phosphorylation and, in a FAK-dependent manner, raised TIE-1, MMP-9, VE-cadherin, angiopoietin-2, and VEGFR1 — a coherent pro-angiogenic, pro-mimicry portfolio — while VEGF itself rose independently of FAK, implicating alternative leptin-activated routes such as JAK2/STAT3, MAPK, NF-κB, and HIF-1α. In MCF-7 cells, the induction of MMP-9 required FAK, whereas angiopoietin-2 did not, and TIE-1 and VE-cadherin were unchanged. The researchers caution that mimicry identification rests on morphology and staining, and that future studies must confirm functional, perfusable lumens to rule out simple matrix deposition.

The translational implications are difficult to dismiss. Obesity drives leptin upward in proportion to fat mass, and hyperleptinemia is strongly associated with poor breast cancer prognosis, making the leptin–FAK axis an attractive therapeutic target, particularly in leptin-responsive tumors. The authors propose that combining FAK inhibitors with the anti-angiogenic drugs already in clinical use could yield additive or even synergistic effects by closing both escape routes simultaneously. They are equally candid about the caveats: the CAM assay, however elegant, lacks the immune and stromal complexity of human tumors; only two cell lines were examined, limiting extrapolation to other molecular subtypes; and no mammalian in vivo model was used, so systemic physiology remains untested. Orthotopic models and patient-derived xenografts, the team notes, will be essential to confirm the pathway’s role in living animals, and the variability of physiological leptin levels across metabolic states — obesity included — could reshape the magnitude of these responses in patients.

Conceptually, the study elevates leptin from metabolic bystander to active architect of tumor vascular plasticity: one hormone, two levers — angiogenesis and vasculogenic mimicry — pulled differently across two breast cancer subtypes with distinct survival strategies. It carries a poignant human footnote as well. The paper is dedicated to Dr. Napoleón Navarro-Tito, who conceived and directed the project at the Universidad Autónoma de Guerrero and died in July 2025, before seeing it published. If the leptin–FAK circuit is validated in patients, the work may come to be remembered as an early map of a vulnerability at the border between metabolism and malignancy — the exact point where the body’s energy reserves, quite literally, feed a tumor’s bloodline.

Vasculogenic mimicry is a unique ability of cancer cells to form vessel-like structures that enable tumor growth and metastasis. This phenomenon is particularly significant in aggressive tumors like lung adenocarcinoma, where traditional angiogenesis—the formation of new blood vessels from pre-existing ones—falls short. The identification of VM has introduced new paradigms in the understanding of tumor vascularity and has led researchers to explore the underlying genetic factors that contribute to this process.

In their investigation, the authors employed a variety of experimental techniques to analyze the expression levels of DCN, NPM3, and SULF1 in lung adenocarcinoma specimens. Through comprehensive bioinformatics analysis, they were able to determine that these genes serve as key regulators of VM. Notably, the study revealed that elevated expression of these hub genes correlates with poorer patient outcomes, suggesting a potential prognostic value linked to VM in lung cancer patients.

The study goes beyond mere observational analysis; it delves into the mechanistic intricacies of how these genes contribute to the establishment of vasculogenic mimicry. DCN, known for its role in extracellular matrix remodeling, was found to interact with key signaling pathways that promote tumor cell motility and invasiveness. By influencing the microenvironment surrounding the tumor, DCN facilitates the adaptation of cancer cells to hypoxic conditions, ultimately fostering the formation of vessel-like structures.

Similarly, NPM3, which is associated with various cellular processes including gene expression and nucleolar dynamics, has emerged as a pivotal player in the modulation of vascular mimicry. The research findings indicate that NPM3 influences the activation of signaling pathways crucial for VM, highlighting its potential as a therapeutic target. The role of SULF1, an enzyme involved in the modification of heparan sulfate proteoglycans, adds another layer to this complex interaction, further elucidating how these genes interconnect to promote tumor survival and progression through VM.

The implications of these findings are significant, not only for the scientific understanding of lung adenocarcinoma but also for clinical applications. With the identification of DCN, NPM3, and SULF1 as key players in vasculogenic mimicry, there exists an opportunity for the development of targeted therapies aimed at disrupting these molecular pathways. Such interventions could enhance the efficacy of existing treatment modalities and improve patient prognoses.

Moreover, the study encourages further investigation into the role of vasculogenic mimicry in other cancer types. Given the universal challenge of tumorigenesis, exploring similar genetic signatures across various malignancies could uncover shared vulnerabilities and lead to the establishment of pan-cancer therapeutic approaches. This kind of research could significantly shift paradigms in oncology, moving away from broad-spectrum chemotherapy toward more personalized medicine strategies that target specific genetic alterations driving malignancy.

The increasing recognition of the importance of the tumor microenvironment in cancer biology cannot be overstated. As cancers evolve, they adapt not only to the host’s immune responses but also to the architectural and biochemical cues from their surroundings. By unraveling the genetic components implicated in these processes, researchers can gain a better understanding of cancer development and progression, ultimately guiding the design of more effective therapies.

The study by Sun and colleagues serves as a catalyst for future research initiatives aimed at unraveling the complexities of cancer biology. The findings have already garnered interest from the broader scientific community, prompting discussions about the feasibility of translating these insights into clinical practice. Collaborative efforts among researchers, clinicians, and biopharmaceutical companies will be essential to explore the therapeutic potential of targeting DNC, NPM3, and SULF1.

As the landscape of cancer research grows increasingly intricate, the importance of interdisciplinary approaches becomes more apparent. By bridging the gap between basic research and clinical application, scientists can accelerate the development of new therapeutics. This study stands as a testament to the potential that lies in understanding the genetic underpinnings of cancer, particularly in the context of aberrant processes like vasculogenic mimicry.

In conclusion, the findings from this research illuminate critical pathways that contribute to the aggressiveness of lung adenocarcinoma and provide new avenues for innovative treatment strategies. The identification of DCN, NPM3, and SULF1 as hub genes related to vasculogenic mimicry marks a significant step forward in unraveling the complexities of cancer biology and developing more targeted therapeutic interventions. As research progresses, the hope is that these discoveries will translate into improved outcomes for patients battling this devastating disease.

Subject of Research: The relationship between hub genes DCN, NPM3, and SULF1 and vasculogenic mimicry in lung adenocarcinoma.

Article Title: DCN, NPM3 and SULF1 are hub genes related to vasculogenic mimicry in lung adenocarcinoma.

Article References:

Sun, C., Ye, M., Cao, W. et al. DCN, NPM3 and SULF1 are hub genes related to vasculogenic mimicry in lung adenocarcinoma.
J Cancer Res Clin Oncol 151, 318 (2025). https://doi.org/10.1007/s00432-025-06361-0

Image Credits: AI Generated

DOI: https://doi.org/10.1007/s00432-025-06361-0

Keywords: lung adenocarcinoma, vasculogenic mimicry, cancer genetics, DCN, NPM3, SULF1, targeted therapy, tumor microenvironment.