Regeneration: The origin of cancer or a possible cure?

Abstract

A better understanding of the forces controlling cell growth will be essential for developing effective therapies in regenerative medicine and cancer. Historically, the literature has linked cancer and tissue regeneration-proposing regeneration as both the source of cancer and a method to inhibit tumorigenesis. This review discusses two powerful regeneration models, the vertebrate urodele amphibians and invertebrate planarians, in light of cancer regulation. Urodele limb and eye lens regeneration is described, as well as the planarian's emergence as a molecular and genetic model system in which recent insights begin to molecularly dissect cancer and regeneration in adult tissues.

Figure 1. Links between regeneration and cancer

(A) Regenerative events and their corollaries in cancer. Importantly, the process of regeneration can be repeated without causing malignant transformation, while in cancer the regenerative process is incomplete such that chronic injury and inflammation leads to continuous proliferation. This suggests that characterizing signals at later stages of regeneration (especially those involved in termination) may help identify candidates able to stop abnormal proliferative responses to chronic injury. (B) Regeneration can correct malignant transformation, as in newt limbs where amputation through the site of induced tumors results in the regeneration of a normal limb without tumors ([16, 21, 57] and references therein).

Figure 2. Differential carcinogenic responses in regenerating versus non-regenerating tissues

(A) Vertebrates Newt dorsal iris regenerates while ventral iris does not. Lens removal and dorsal iris regeneration into lens (top row, adapted from [14]). Treatment with carcinogens causes (second row) supernumerary lenses to arise from the ventral iris [50], or (third row) inhibition of lens regeneration and ventral iris-derived tumors (light red) [26]. (B) Invertebrates. In one planarian with limited regenerative abilities (Dendrocoelum lacteum), anterior tissue regenerates while posterior tissue does not. Anterior treatment with carcinogens causes mild differentiated hyperplasia but posterior exposure induces infiltrating tumors (adapted from [16]). Remarkably, decapitation of worms with posterior tumors leads to tumorigenic tissue differentiating into accessory pharynx, suggesting that long-range signaling during regeneration could modulate the behavior of aberrant cells [16]. In both cases (A and B), regenerative tissue is more resistant to carcinogenesis than non-regenerating tissue.

Figure 3. Loss of planarian PTEN leads to growth aberrations

S. mediterranea PTEN loss-of-function by RNAi. (A–C) Smed-PTEN RNAi effects: (A) loss of tissue maintenance, (B) basement membrane disruption (green arrows) and the presence of invasive cells (sections stained with hematoxilin and eosin), and (C) an increase in proliferative activity (sections stained with the nuclei marker green sytox) and mitotic cells (red dots). Insets show the transformation of the epithelial monolayer into a multilayer. (D, E) Rapamycin treatment compensates for Smed-PTEN loss of function, (D) preventing abnormal proliferation while keeping basal tissue-maintenance levels and (E) restoring regeneration capabilities. Data from [72].