The potential of the tumor microenvironment to influence Apo2L/TRAIL induced apoptosis
Thomas A Mace1, Nariyuke Yamane, Jinrong Cheng
1Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Abstract:
Apo2L/TRAIL ligation of specific cell surface receptors (DR4 and DR5) induces apoptosis of many malignant cells with little effect on normal cells. This anti-tumor capability has been demonstrated using cell lines of many tumor types, both in vitro and in vivo when the cells are grown as xenografts. We have extended these studies to investigate the efficacy of Apo2L/TRAIL against patient tumor xenografts in SCID mice and found that the growth of many tumors, both of primary and metastatic origin, can be inhibited by Apo2L/TRAIL. The basis of resistance to Apo2L/TRAIL induced apoptosis in malignant cells and normal cells is not completely understood, but it is known that a variety of factors including hypoxia, MMPs and cytokines present in the tumor microenvironment can influence the response of malignant cells to Apo2L/TRAIL. Currently, the clinical potential of several molecules targeting the Apo2L/TRAIL receptors DR4 and DR5 is being investigated. Our goal in this review is to provide a brief overview of a number of factors that have potential to influence the response of patient tumors to Apo2L/TRAIL.
Insights
Apo2L/TRAIL induces apoptosis in many cancer cells, inhibiting tumor growth in patient xenografts. Understanding resistance factors in the tumor microenvironment is key for effective cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Apo2L/TRAIL induces apoptosis in malignant cells via DR4/DR5 receptors, sparing normal cells.
- Previous studies demonstrated anti-tumor effects in vitro and in vivo xenografts.
- Tumor microenvironment factors can influence Apo2L/TRAIL resistance.
Purpose of the Study:
- To review factors influencing patient tumor response to Apo2L/TRAIL.
- To explore the efficacy of Apo2L/TRAIL against patient-derived xenografts.
- To highlight the clinical potential of targeting DR4 and DR5 receptors.
Main Methods:
- Investigated Apo2L/TRAIL efficacy in SCID mouse models with patient tumor xenografts.
- Reviewed literature on tumor microenvironment factors affecting Apo2L/TRAIL response.
- Examined resistance mechanisms to Apo2L/TRAIL-induced apoptosis.
Main Results:
- Apo2L/TRAIL inhibited the growth of primary and metastatic patient tumors in xenografts.
- Identified hypoxia, MMPs, and cytokines as potential modulators of Apo2L/TRAIL efficacy.
- Confirmed Apo2L/TRAIL's selective toxicity towards malignant cells.
Conclusions:
- Apo2L/TRAIL shows promise as an anti-cancer therapeutic, particularly against patient tumors.
- Further research into tumor microenvironment interactions is crucial for optimizing Apo2L/TRAIL therapy.
- Targeting DR4 and DR5 receptors holds significant clinical potential for cancer treatment.
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