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Published on: August 2, 2022
Therapy of hematogenous melanoma brain metastases with endostatin
Matthias Kirsch1, Patrick Weigel, Thomas Pinzer
1Department of Neurosurgery, Carl Gustav Carus University Hospital, Technical University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. matthias.kirsch@uniklinikum-dresden.de
Purpose:
Cerebral metastases represent the most common type of brain tumors. This study investigated the effects of endogenous endostatin on hematogenous cerebral melanoma metastases.
Experimental Design:
Murine K1735 melanoma cells were transfected with the mouse endostatin cDNA. Experimental tumors were induced either by s.c. injection, intracerebral implantation, or via injection into the internal carotid artery to simulate hematogenous metastatic spread. The effects of endostatin expression on tumor incidence, growth pattern, and vascularity were analyzed.
Results:
In vitro secretion of endostatin by 2.5 x 10(5) cells within 24 hours was 0.12 +/- 0.03 ng, 4.35 +/- 0.4, and 1.18 +/- 0.7 ng/mL for wild type and two endostatin-transfected K1735 clones termed K1735-endo/2 and K1735-endo/8, respectively. Tumor inhibition in vivo correlated with endogenous endostatin production. Within 25 days, growth of s.c. K1735-endo/2 tumors was <20% compared with wild-type controls. Following intracerebral implantation the average survival time of mice was 27.8 +/- 2.6 versus 13.3 +/- 3.7 days in the K1735-endo/2 versus the wild-type group, respectively. Intracarotid injection of 1 x 10(5) wild-type cells killed the mice within 24 +/- 1.8 days. In contrast, endostatin expression prevented macroscopic metastatic tumor growth in 11 of 12 mice, although viable microscopic tumor pockets were detectable in all animals.
Conclusion:
Endostatin inhibits tumor progression of multiple cerebral metastases in vivo. Hematogenous micrometastases are more efficiently suppressed than tumors resulting from high focal cell numbers which may be due to a higher angiogenic signaling exerted by massive cell deposits. Endostatin may prevent solid tumor growth more effectively by inhibition of early angiogenesis.
Insights
Endogenous endostatin significantly inhibits the growth of cerebral melanoma metastases in mice. This protein is more effective at suppressing early-stage, hematogenous micrometastases than larger tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cerebral metastases are the most common brain tumors.
- Understanding mechanisms to inhibit brain tumor growth is crucial.
Purpose of the Study:
- To investigate the effects of endogenous endostatin on hematogenous cerebral melanoma metastases.
- To assess endostatin's potential in preventing or treating brain metastases.
Main Methods:
- Murine K1735 melanoma cells were genetically modified to express mouse endostatin.
- Tumors were induced via subcutaneous injection, intracerebral implantation, or internal carotid artery injection to mimic metastatic spread.
- Tumor incidence, growth, and vascularity were analyzed in relation to endostatin expression.
Main Results:
- Endostatin-transfected melanoma cells secreted varying levels of endostatin in vitro.
- Endogenous endostatin production correlated with significant tumor inhibition in vivo.
- Mice with endostatin-expressing tumors showed increased survival and reduced macroscopic tumor growth, particularly after intracarotid injection.
Conclusions:
- Endostatin effectively inhibits the progression of multiple cerebral metastases in vivo.
- Hematogenous micrometastases are more susceptible to endostatin than larger, established tumors.
- Endostatin may prevent solid tumor growth by inhibiting early angiogenesis.
