Cyclooxygenase-2: A Role in Cancer Stem Cell Survival and Repopulation of Cancer Cells during Therapy.

Lisa Y Pang,David J Argyle,Emma A Hurst

doi:10.1155/2016/2048731

Lisa Y Pang, David J Argyle + Show 1 more

Open Access

https://doi.org/10.1155/2016/2048731

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Abstract

Cyclooxygenase-2 (COX-2) is an inducible form of the enzyme that catalyses the synthesis of prostanoids, including prostaglandin E2 (PGE2), a major mediator of inflammation and angiogenesis. COX-2 is overexpressed in cancer cells and is associated with progressive tumour growth, as well as resistance of cancer cells to conventional chemotherapy and radiotherapy. These therapies are often delivered in multiple doses, which are spaced out to allow the recovery of normal tissues between treatments. However, surviving cancer cells also proliferate during treatment intervals, leading to repopulation of the tumour and limiting the effectiveness of the treatment. Tumour cell repopulation is a major cause of treatment failure. The central dogma is that conventional chemotherapy and radiotherapy selects resistant cancer cells that are able to reinitiate tumour growth. However, there is compelling evidence of an active proliferative response, driven by increased COX-2 expression and downstream PGE2 release, which contribute to the repopulation of tumours and poor patient outcome. In this review, we will examine the evidence for a role of COX-2 in cancer stem cell biology and as a mediator of tumour repopulation that can be molecularly targeted to overcome resistance to therapy.

Highlights

To date, intensive cancer research has culminated in an increased knowledge of primary tumour formation, the development of sophisticated therapies, and prolonged survival time of cancer patients
There is growing evidence that cancer is a stem cell disease, where tumours are composed of a mixture of genetically and functionally distinctive cells that contribute to tumour outgrowth, and a small population of cancer stem cells (CSCs) that can drive tumour initiation, therapy resistance, tumour repopulation, and metastasis
We have shown that COX-2 expression is elevated 141-fold in the CSC population compared to the non-CSC population of canine osteosarcoma cells, and that COX-2 inhibition induced a dose-dependent decrease in sphere forming ability, indicating that COX-2 plays a major role in tumour initiation [13]

Summary

Introduction

Intensive cancer research has culminated in an increased knowledge of primary tumour formation, the development of sophisticated therapies, and prolonged survival time of cancer patients. A definitive cure for cancer patients will rely upon further molecular dissection and targeting of these two processes In this regard, there is growing evidence that cancer is a stem cell disease, where tumours are composed of a mixture of genetically and functionally distinctive cells that contribute to tumour outgrowth, and a small population of cancer stem cells (CSCs) that can drive tumour initiation, therapy resistance, tumour repopulation, and metastasis. An oncogenic change can drive tumour-promoting inflammation in tumours that are epidemiologically unrelated to overt inflammatory conditions [22, 23] This “smoldering” inflammation in the microenvironment has many tumourpromoting effects including tissue remodelling, angiogenesis, cancer cell survival, metastasis, and immune evasion [21, 24]. We will focus on the role of COX-2 in cancer stem cell biology, and as a mediator of tumour repopulation, and resistance to therapy

COX-2 Plays a Central Role in Cancer

Mechanisms of Resistance to Therapy

Implications for Cancer Management and Therapy

Conclusions