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Researchers at the Indian Institute of Science Education and Research (IISER), Kolkata, have identified a Vascular Endothelial Growth Factor Receptor (VEGFR) that could pave the way for developing new treatments for colon and renal cancers. This breakthrough has significant implications for both malignant and non-malignant diseases by targeting the process of blood vessel formation, which is crucial for tumor growth and metastasis.
The VEGFR family plays a crucial role in generating new blood vessels, a process essential for embryonic development, wound healing, tissue regeneration, and tumour formation. By manipulating these receptors, scientists aim to develop therapies that inhibit blood supply to tumors, effectively starving and shrinking them.
The study, published in the journal Nature Communications, revealed intriguing differences between two members of the VEGFR family: VEGFR1 and VEGFR2. According to Dr. Rahul Das from the Department of Biological Sciences, VEGFR2 can be spontaneously activated without its ligand, making it the primary receptor for blood vessel formation. In contrast, VEGFR1 remains inactive even when overexpressed in cells, unless it binds to its ligand, VEGF-A, with a ten-fold higher affinity than VEGFR2.
This unique behavior of VEGFR1, often described as a ‘dead enzyme,’ plays a critical role in cancer biology. Upon binding with its ligand, VEGFR1 undergoes transient kinase activation, which is known to contribute to cancer-associated pain, tumor cell survival in breast cancer, and the migration of colorectal cancer cells.
The IISER Kolkata team delved deeper to understand why VEGFR1 remains autoinhibited while VEGFR2 does not. Their investigation uncovered a unique ionic latch in VEGFR1 that is not present in VEGFR2. This ionic latch maintains VEGFR1 in an autoinhibited state by hooking the juxtamembrane segment onto the kinase domain, thus stabilizing its inactive form.
By uncovering the mechanisms of this autoinhibition, the researchers have opened up new avenues for targeted cancer therapies. Treatments that can modulate this latch mechanism could selectively inhibit VEGFR1 activity, potentially reducing cancer cell migration and survival.
This study highlights the intricate balance of cellular mechanisms in cancer progression and offers hope for more effective treatments. As research progresses, these findings could lead to the development of novel therapeutic strategies, significantly impacting the fight against colon and renal cancers.
