An international collaboration led by researchers at the University of Barcelona in Spain has identified the cause behind the two most common forms of the disease Non-small cell lung cancer NSCLC – lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) – respond differently to antiangiogenic treatments that target the blood vessels tumors need to grow. The study found that fibroblasts in the tumor microenvironment play a key role in blood vessel formation, oxygen availability, and response to treatment. results, Published in the magazine Cell death and diseasecould pave the way for treatment decisions that are guided not only by tumor type but also by characteristics of the tumor microenvironment.
“The study reveals that the fibroblast-rich tumor microenvironment is not just a bystander, but a key player in shaping tumor progression. Tumor-associated fibroblasts can influence the vascular network, the availability of oxygen and nutrients, and perhaps also metastatic dissemination and the immune response,” said lead researcher Jordi Alcaraz, Ph.D., professor at the Faculty of Medicine and Health Sciences of the University of Barcelona and researcher at the Bioengineering Institute of Barcelona. Catalonia.
The new study provides additional evidence that can be used to confirm the feasibility of combining antiangiogenic therapies with immunotherapy. Interest in this potential combination therapy has increased over the past few years, to address the limited success of immunotherapy alone in treating NSCLC. Antiangiogenic therapies are of interest as neovascularization has been shown to contribute to immunosuppression and treatment resistance. But while antiangiogenic drugs have shown benefits in treating lung adenocarcinoma, their effectiveness has been limited or produced toxicity as a treatment for squamous cell carcinoma.
“These contradictory results and the limited overall therapeutic benefits achieved by antiangiogenic drugs in LUAD (adenocarcinoma) underscore the need for a more precise understanding of the histotype-dependent complexity of angiogenesis regulation in non-small cell lung cancer,” the researchers wrote.
In this study, the international team analyzed markers of angiogenesis and hypoxia across multiple groups of patients. They used a combination of transcriptomic analyzes in both in vitro and animal studies to examine how tumor-associated fibroblasts regulate angiogenesis in the two main subtypes of lung cancer.
The data showed clear differences between the two cancers. Adenocarcinomas had greater angiogenesis, larger vascular lumina, higher oxygen availability, and less necrosis and hypoxia, whereas squamous cell carcinomas showed poor angiogenesis, increased hypoxia, and more necrotic tissue.
The researchers determined that fibroblasts from adenocarcinomas produced a pro-angiogenic secretion characterized by elevated levels of vascular endothelial growth factor A (VEGF-A) and tissue inhibitor of metalloproteinase-1 (TIMP-1). “The LUAD-TAF secretome is primed for angiogenesis through SMAD3-dependent overproduction of key regulators, especially TIMP-1 and VEGF-A,” the researchers wrote, adding, “We also discovered a novel function for TIMP-1 in promoting endothelial cell hyperbranching via basal VEGF signaling.” The results showed that TIMP-1 amplified VEGF-driven angiogenesis and increased the formation of branching blood vessel networks commonly associated with tumors.
However, in squamous cell carcinoma, fibroblasts behave differently. “In contrast, in squamous cell carcinoma, angiogenesis is ineffective due to molecular changes in associated fibroblasts resulting from high tobacco exposure, giving rise to tumors with lower oxygen levels, i.e. greater hypoxia,” Alcaraz said.
The findings may also help explain differences in disease progression between the two cancers. Because metastasis depends on cancer cells reaching blood vessels, the more developed vascular networks in adenocarcinoma likely play a role in its tendency to metastasize earlier than in squamous cell carcinoma.
These findings could influence new approaches to stratification and treatment selection for patients with NSCLC. Potential biomarkers include SMAD3/SMAD2 ratio, TIMP-1 levels, VEGF-A expression, and hypoxia-associated fibroblast signatures. The researchers suggest that patients with adenocarcinoma may benefit from therapies targeting stromal SMAD3 or TIMP-1 signaling, while patients with squamous cell carcinoma may benefit more from therapies designed to counteract hypoxia, acidosis, or other features of the tumor microenvironment.
Future research will focus on validating biomarkers such as TIMP-1 in larger patient cohorts and prospective studies, better understanding the molecular interactions linking SMAD3, VEGF-A, and TIMP-1, and developing therapies targeting these pathways. As Alcaraz noted, the challenge now is to identify robust biomarkers, validate them prospectively, and demonstrate that modulating the tumor microenvironment can improve therapeutic responses.
