Tumor Microenvironment Drives Differential Anti-Angiogenic Response in Lung Cancer Subtypes, Study Finds
Key Insights
A University of Barcelona study reveals that tumor-associated fibroblasts drive the divergent responses to anti-angiogenic therapy between lung adenocarcinoma (search) and squamous cell carcinoma (search).
Adenocarcinoma exhibits active angiogenesis supported by fibroblast-driven synergy between VEGF and TIMP-1 (search), while squamous carcinoma shows inefficient vessel formation and a more hypoxic, acidic environment.
The findings suggest that squamous cell carcinoma (search)'s historical exclusion from combined immunotherapy and anti-angiogenic strategies may be explained by these microenvironmental differences.
A new study led by the University of Barcelona has uncovered why the two predominant forms of lung cancer—adenocarcinoma and squamous cell carcinoma (search)—exhibit starkly different responses to anti-angiogenic therapy. Published in Cell Death & Disease, the research demonstrates that the tumor microenvironment, particularly cancer-associated fibroblasts, plays a decisive role in shaping vascular network formation, oxygen availability, and ultimately drug resistance.
"The study reveals that the fibroblast-rich tumor microenvironment is not merely a spectator but a key player that shapes the tumor's progression," said Jordi Alcaraz, professor at the UB's Faculty of Medicine and Health Sciences and researcher at the Institute for Bioengineering of Catalonia (IBEC), the Hospital Clínic de Barcelona, and CIBERES, who led the research. "Tumor-associated fibroblasts can influence the vascular network, the availability of oxygen and nutrients and, potentially, also metastatic dissemination and the immune response."
The international collaboration involved experts from the Catalan Institute of Oncology, the Bellvitge Biomedical Research Institute (IDIBELL), the Mayo Clinic in the United States, the Francis Crick Institute in the United Kingdom, and the Garvan Institute of Medical Research and the University of New South Wales in Australia. The first author is UB researcher Natalia Díaz Valdivia.
Fibroblasts as Architects of Tumor Vasculature
To dissect the mechanistic underpinnings of differential drug response, the research team analyzed multiple markers associated with blood vessel formation and oxygen deprivation across the main lung cancer subtypes. Their findings, validated in both patient samples and animal models, revealed that adenocarcinoma exhibits significantly more active and functional angiogenesis, characterized by higher oxygen levels and reduced cell death. In contrast, squamous cell carcinoma (search) displays poor intratumoral blood vessel formation and a more acidic, hypoxic microenvironment.
"We have observed that, in adenocarcinoma, these fibroblasts promote the formation of blood vessels through a synergy between vascular endothelial growth factor (search) and TIMP-1 (search), a novel proangiogenic factor," Alcaraz explained. Conversely, in squamous cell carcinoma (search), blood vessel formation is inefficient due to molecular changes in associated fibroblasts resulting from higher tobacco exposure, yielding tumors with lower oxygen levels.
Implications for Immunotherapy Combinations
Lung cancer remains the leading cause of cancer-related death worldwide. Immunotherapy, which boosts the immune system's capacity to attack cancer cells, represents one of the most promising therapeutic approaches, yet most patients fail to respond. One proposed strategy to enhance immunotherapy efficacy involves combining it with anti-angiogenic drugs that normalize tumor blood vessels and reduce immune suppression.
"Until now, squamous cell carcinoma (search), the second most common type of lung cancer, has been excluded from this promising combined therapeutic strategy because it has historically shown resistance to anti-angiogenic therapies, unlike lung adenocarcinoma (search), which is the most common subtype," noted Alcaraz.
The study's findings provide a mechanistic explanation for this exclusion. The enhanced angiogenesis observed in adenocarcinoma also offers a straightforward rationale for why these tumors tend to metastasize earlier than squamous cell carcinoma (search), as metastasis requires tumor cells to access the blood vessel network for dissemination.
Toward Microenvironment-Guided Precision Therapy
The researchers argue that these microenvironmental differences reinforce the need for distinct therapeutic strategies tailored to each lung cancer subtype. "Especially now that combinations of immunotherapy and anti-angiogenic drugs play a central role in oncology," Alcaraz added.
Rather than applying uniform treatment approaches, the team proposes incorporating both angiogenesis status and tumor microenvironment characteristics as criteria for patient stratification and treatment selection. This could involve biomarkers such as TIMP-1 (search) to identify tumors dependent on specific pro-angiogenic molecular pathways, as well as rational combinations of immunotherapy with microenvironment-targeted agents.
"For example, our results suggest that adenocarcinoma might benefit more from treatments targeting specific pro-angiogenic pathways such as SMAD3 (search) or TIMP-1 (search), whereas in squamous cell carcinoma (search) it may be more relevant to target tumor hypoxia or acidosis," Alcaraz said.
The researchers also highlight the urgent need to develop new therapeutic approaches against TIMP-1 (search) in adenocarcinoma, given that no specific inhibitor currently exists. Looking forward, Alcaraz emphasized that the major challenge is translating these discoveries into clinical practice: "[We need] to identify robust biomarkers, such as TIMP-1, validate them prospectively and demonstrate that modulating the tumor microenvironment can truly improve patients' therapeutic response."
This study was partially funded by grants from the Spanish National Research Council, the European Union's Horizon 2020 research and innovation programme, and the Spanish Association Against Cancer.