• cancer

A principal feature of many cancer cells is that they can evade apoptosis. Work in flies investigates whether this characteristic can be an initiating step in the development of cancer: it has been shown that apoptosis-deficient calls are susceptible to becoming tumorigenic after stress events that are inconsequential in tissues in which apoptotic pathways are not compromised.

Initiation of apoptosis was prevented in imaginal discs using mutations in the caspase Dmel\Dronc or other pro-apoptotic genes; the JNK responses after various stress-inducing events [X-rays, a pulse of p53, or a pulse of JNK (bsk) itself] were assessed. Persistent JNK activity after a transient initiation event is observed, resulting in tissue overgrowth.

The constitutively active Ras85D mutation, Ras85D^V12, is analogous to oncogenic mutations found in human RAS proteins. Typically, the Ras85D^V12 activated mutation produces mild overproliferation phenotypes. In apoptosis-deficient cells in which this activated RAS mutation is expressed, a stress event results in much more dramatic overgrowth. See also the human disease model report 'cancer, multiple, RAS-related' (FBhh0000474).

In related experiments, apoptosis was compromised in imaginal discs by mutation in the caspase Dmel\Drice gene or by expressing the caspase inhibitor BacA\p35. After X-irradiation, a number of tumorigenic phenotypes are observed: overgrowth and atypical migration of apoptosis-deficient cells; delamination of the epithelium; ectopic expression of wg (a measure of JNK signaling).

Assayed in wing discs, co-expression of BacA\p35 and Dmel\hid (normally an activator of apoptosis) results in sub-apoptotic caspase activation. This results in several phenotypes indicative of tumorigenic changes: cell invasion outside the restricted region of expression and elevated matrix metalloproteinase (Mmp1) expression (invading tumor cells typically express MMPs to degrade the extracellular matrix and basement membrane); caspase activation of JNK signaling plays a role in this process. These results support the hypothesis that effector caspase activity below levels sufficient to cause cell death play an important role in tumorigenesis.

[updated Jun. 2019 by FlyBase; FBrf0222196]