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Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression.

ABSTRACT: Non-canonical secretion pathways, collectively known as unconventional protein secretion (UPS), are alternative secretory mechanisms usually associated with stress-inducing conditions. UPS allows proteins that lack a signal peptide to be secreted, avoiding the conventional endoplasmic reticulum-Golgi complex secretory pathway. Molecules that generally rely on the canonical pathway to be secreted may also use the Golgi bypass, one of the unconventional routes, to reach the extracellular space. UPS studies have been increasingly growing in the literature, including its implication in the biology of several diseases. Intercellular communication between brain tumor cells and the tumor microenvironment is orchestrated by various molecules, including canonical and non-canonical secreted proteins that modulate tumor growth, proliferation, and invasion. Adult brain tumors such as gliomas, which are aggressive and fatal cancers with a dismal prognosis, could exploit UPS mechanisms to communicate with their microenvironment. Herein, we provide functional insights into the UPS machinery in the context of tumor biology, with a particular focus on the secreted proteins by alternative routes as key regulators in the maintenance of brain tumors.

SUBMITTER: Iglesia RP

PROVIDER: S-EPMC9242006 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Endpoints related to tumor progression are commonly used in clinical trials of novel therapeutic agents for neuroendocrine tumors (NETs). Whether improved tumor control translates into improved overall survival (OS), however, is uncertain. We assessed associations between tumor progression endpoints and OS in observational cohorts of patients with advanced neuroendocrine tumors treated with somatostatin analogs or with everolimus. We identified 440 patients with advanced NET who had received treatment with single-agent somatostatin analogs and 109 patients treated with everolimus, all of whom were treated at our institution and were evaluable for both tumor progression and survival. We assessed associations between progression-free survival (PFS) and OS by using the Kendall tau test, and we assessed associations between tumor progression and OS by using a landmark analysis. In the 440 patients treated with somatostatin analogs, we observed a significant correlation between PFS and OS by using the Kendall tau test (0.31; p < .0001). Additionally, the development of progressive disease was associated with OS in a landmark analysis, at landmark times of 6, 12, 18, and 24 months. In the 109 patients treated with everolimus, we similarly observed a significant correlation between PFS and OS by using the Kendall tau test (0.44; p < .0001) and associations between progressive disease and OS by using a landmark analysis at 3, 6, and 12 months. In these observational cohorts of patients with metastatic NET treated with single-agent somatostatin analogs or everolimus, longer times to disease progression and longer PFS were both associated with improved OS. Our findings support the continued use of disease progression endpoints in NET clinical trials. The Oncologist 2017;22:165-172Implications for Practice: Clinical trials in patients with advanced neuroendocrine tumors have used progression-free survival as a primary endpoint. While there is a general assumption that slowing or halting tumor growth is beneficial, little direct evidence links improvements in progression endpoints to improvements in overall survival. This study assessed associations between tumor progression endpoints and overall survival in observational cohorts of patients with advanced neuroendocrine tumor treated with somatostatin analogs or everolimus. Longer times to disease progression and improved progression-free survival were both associated with improved overall survival. The findings support the continued use of tumor progression endpoints in clinical trials for neuroendocrine tumors.

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Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression.

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