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26 January 2025

Targeting Interleukin-6 Offers New Hope For Gastric Cancer Treatment

Study finds anti-IL-6 treatment could inhibit peritoneal metastasis progression caused by cancer-associated fibroblasts.

Researchers have made significant strides toward developing new therapeutic strategies for gastric cancer, particularly targeting peritoneal metastasis (PM), which often complicates treatment options. A recent study published found promising evidence indicating how interleukin-6 (IL-6), secreted by cancer-associated fibroblasts (CAFs), plays a pivotal role in this metastatic process.

Gastric cancer is notorious for its aggressive nature and high recurrence rates, with PM being one of the most common forms of distant metastasis. Traditional treatment methods, including systemic chemotherapy, often fall short due to the unique conditions present within the tumor microenvironment (TME). This study, conducted by researchers at Okayama University Hospital, sought to unravel the mechanisms through which CAFs and IL-6 contribute to the progression of PM.

Previous findings have underscored the importance of the TME, where CAFs not only influence tumor growth but also modulate the immune responses within the tumor. This research focused on the interactions between CAFs and gastric cancer cells, showing how these interactions can lead to enhanced IL-6 secretion, which contributes to tumor progression and chemoresistance.

Through immunohistochemical analysis of clinical gastric cancer samples, the researchers established a significant correlation between high IL-6 levels and poor patient prognosis. Specifically, they found through their studies involving 168 patients treated between 2002 and 2007, higher IL-6 expression was linked with increased α-smooth muscle (α-SMA) levels, which is recognized as a marker for CAFs. This connection reinforces the notion of IL-6 as not only a promising therapeutic target but also as a marker for assessing disease severity.

The study also revealed compelling results from murine models, where the researchers co-inoculated gastric cancer cells with fibroblasts. They observed significantly increased tumor growth in these CAF-rich environments compared to cancer cells alone. Notably, treatment with anti-IL-6 receptor antibodies (anti-IL-6R Ab), such as MR16-1, inhibited tumor progression prominently within these CAF-inclusive contexts.

"IL-6 expression was significantly correlated with α-SMA expression and associated with poor prognosis of gastric cancer," the authors of the article noted, highlighting the importance of IL-6 levels as potential indicators of treatment efficacy.

When they treated their model with anti-IL-6R Ab, the results indicated a marked inhibition of tumor progression, providing insight and hope for clinical applications. The data prominently illustrated, "Anti-IL-6R Ab could inhibit PM of GC by the blockade of IL-6 secreted by CAFs, which suggests its therapeutic potential for PM of gastric cancer,” reinforcing the role of IL-6 as a therapeutic target.

This findings point to the possibility of combining anti-IL-6R Ab with standard chemotherapy regimens, potentially overcoming the resistance commonly seen with conventional treatments. Yet, the study does urge caution, noting the need for more extensive clinical trials to validate these findings, particularly concerning the parallel effectiveness of therapies without CAF involvement.

Overall, this research opens the door to new avenues for treating gastric cancer, especially those patients with PM, by targeting specific mechanisms within the TME. It highlights IL-6 as not only a marker for prognosis but as a probable pivot for therapeutic intervention. Future research could potentially lead to improved outcomes for patients suffering from this difficult-to-treat disease.