RET mutation and increased angiogenesis in medullary thyroid carcinomas

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Advanced medullary thyroid cancers (MTCs) are treated with tyrosine kinase inhibitors targeting angiogenesis.
• Treatment response varies, necessitating identification of MTCs likely to benefit from these therapies.
• The role of RET mutations in MTC microvasculature remains unclear.

Purpose of the Study:

• To investigate the influence of RET mutations on angiogenesis and vascular characteristics in medullary thyroid cancers.
• To compare proangiogenic gene expression and vascular features between RET-mutated (RETmut) and wild-type RET (RETwt) MTCs.

Main Methods:

• Analysis of 45 RETmut and 34 RETwt MTCs.
• Taqman Low-Density Arrays for proangiogenic gene expression.
• Immunohistochemistry for VEGFRs, PDGFs, NOTCH3, CD31, podoplanin, and alpha-smooth muscle actin (α-SMA).
• Assessment of microvessel density (MVD), lymphatic vessel density (LVD), and vascular pericyte density.

Main Results:

• RETmut MTCs showed upregulated proangiogenic gene expression (mRNA and protein), particularly VEGFR1, PDGFB, and NOTCH3, compared to RETwt tumors.
• Microvessel density (MVD) and lymphatic vessel density (LVD) were similar between RETmut and RETwt groups.
• Microvessels in RETmut tumors exhibited significantly higher α-SMA positivity, indicating enhanced pericyte coverage.

Conclusions:

• Angiogenesis in RETmut MTCs appears more intense and complete due to enhanced pericyte stabilization, potentially increasing sensitivity to anti-angiogenic therapy.
• Increased vascular pericyte density in RETmut MTCs suggests a potential benefit from combined or preliminary treatment with PDGF inhibitors.