Cell death-stimulated cell proliferation: a tissue regeneration mechanism usurped by tumors during radiotherapy

Abstract

The death of all the cancer cells in a tumor is the ultimate goal of cancer therapy. Therefore, much of the current effort in cancer research is focused on activating cellular machinery that facilitates cell death such as factors involved in causing apoptosis. However, recently, a number of studies point to some counterintuitive roles for apoptotic caspases in radiation therapy as well as in tissue regeneration. It appears that a major function of apoptotic caspases is to facilitate tissue regeneration and tumor cell repopulation during cancer therapy. Because tumor cell repopulation has been shown to be important for local tumor relapse, understanding the molecular mechanisms behind tumor repopulation would be important to enhance cancer radiotherapy. In this review, we discuss our current knowledge of these potentially paradigm-changing phenomena and mechanisms in various organisms and their implications on the development of novel cancer therapeutics and strategies.

Figure 1

The “Phoenix Rising” pathway of tissue regeneration and wound healing.

Figure 2

Critical roles of caspase 3 in cell death-simulated tumor cell proliferation. About 500 4T1Fluc cells were mixed with 2.5×10⁵ of lethally irradiated, wild type (right hind legs) or casp3−/−(left hind legs) mouse embryonic fibroblast cells and injected subcutaneously into nude mice. The growth of 4T1Fluc cells were then followed by use of bioluminescence imaging. Please note the logarithmic scale of the Y axis. The error bars represent standard error of the means (n=4). The difference between two groups were highly significant statistically (P<0.001 from day 3 on, one-way ANOVA test).

Figure 3

Activated caspase 3 (CC-3) in pretreatment biopsies predicts for A) tumor recurrence in head and neck cancer patients who underwent radiotherapy; B) survival in advanced breast cancer patients who underwent surgery and other treatments.