Wound healing and cancer stem cells: inflammation as a driver of treatment resistance in breast cancer

Abstract

The relationship between wound healing and cancer has long been recognized. The mechanisms that regulate wound healing have been shown to promote transformation and growth of malignant cells. In addition, chronic inflammation has been associated with malignant transformation in many tissues. Recently, pathways involved in inflammation and wound healing have been reported to enhance cancer stem cell (CSC) populations. These cells, which are highly resistant to current treatments, are capable of repopulating the tumor after treatment, causing local and systemic recurrences. In this review, we highlight proinflammatory cytokines and developmental pathways involved in tissue repair, whose deregulation in the tumor microenvironment may promote growth and survival of CSCs. We propose that the addition of anti-inflammatory agents to current treatment regimens may slow the growth of CSCs and improve therapeutic outcomes.

Keywords: cancer stem cells; developmental pathways; inflammation; tumor microenvironment.

Figure 1

Cellular plasticity in normal vs altered homeostasis. (Left panel) Under normal conditions, stem cell/non-stem cell ratios are maintained at a consistent level via slow cycling stem cells (blue), which undergo a unidirectional differentiation to lineage restricted cells. (Right panel) In conditions of altered homeostasis, the ratio of stem cell/non-stem cell is increased by proliferation of stem cells and a bidirectional differentiation whereby lineage restricted cells are able to dedifferentiate and acquire stem-like features. In both wound healing and the tumor microenvironment, this cellular plasticity is driven by inflammatory and developmental factors. However, in wound healing, expression of these factors is transient, homeostasis returns, and the ratio of stem/non-stem cells returns to normal levels. In the tumor microenvironment, continuous expression of these factors may lead to a permanent expansion of stem-like cells.