Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster

Abstract

Loss of cell polarity and cancer are tightly correlated, but proof for a causative relationship has remained elusive. In stem cells, loss of polarity and impairment of asymmetric cell division could alter cell fates and thereby render daughter cells unable to respond to the mechanisms that control proliferation. To test this hypothesis, we generated Drosophila melanogaster larval neuroblasts containing mutations in various genes that control asymmetric cell division and then assayed their proliferative potential after transplantation into adult hosts. We found that larval brain tissue carrying neuroblasts with mutations in raps (also called pins), mira, numb or pros grew to more than 100 times their initial size, invading other tissues and killing the hosts in 2 weeks. These tumors became immortal and could be retransplanted into new hosts for years. Six weeks after the first implantation, genome instability and centrosome alterations, two traits of malignant carcinomas, appeared in these tumors. Increasing evidence suggests that some tumors may be of stem cell origin. Our results show that loss of function of any of several genes that control the fate of a stem cell's daughters may result in hyperproliferation, triggering a chain of events that subverts cell homeostasis in a general sense and leads to cancer.

The emerging role of p53 in stem cells

“…In this context, it is worth noting that symmetric divisions per se may induce aneuploidy, thus further contributing to cancer initiation. This is the case for Drosophila neuroblasts, which become aneuploid upon a few rounds of symmetric divisions [43], probably because the same machinery that controls the modality of SC division also regulates centrosome functions, mitotic spindle orientation and chromosome segregation [44,45]. Opinion…”

Attributes of adult stem cells

“…A further possibility is a mixture of symmetrical and asymmetrical cell divisions ( Figure 3C). Symmetrical stem cell divisions provide a mechanism to increase the stem cell population after stem cell loss, but symmetrical divisions can also lead to a dangerous escalation of stem cell numbers, as seen with disruption of asymmetrical neuroblast cell division in Drosophila melanogaster that leads to lethal, expansive, tumourlike lesions when such cells are transplanted into adult hosts [15]. Alternatively, lack of appropriate signalling can lead to stem cell exhaustion, as seen in mice lacking Tcf-4 and so unable to form β-catenin-Tcf-4 complexes essential for Wnt signalling in the small intestine ( Figure 4) [16].…”

Somatic stem cells and the origin of cancer

“…Normally, Drosophila neuroblasts divide asymmetrically, a process which is controlled by genes regulating cell polarity and cell fate 106,107 . Using Drosophila as a model, three recent studies have shown that the loss of polarity and impairment of asymmetric division in stem cells leads to tumorigenesis [108][109][110] . In these reports, neuroblasts containing mutations in various genes that control cell division (Raps, Mira, Numb, Brat and Pros) developed aggressive tumors that could be retransplanted into new hosts.…”

“…In these reports, neuroblasts containing mutations in various genes that control cell division (Raps, Mira, Numb, Brat and Pros) developed aggressive tumors that could be retransplanted into new hosts. Importantly, asymmetric division was disrupted in mutant stem cells, whereby both daughter cells grow and behave like neuroblasts leading to the formation of tumors [108][109][110] . This transformation was associated with genome instability and centrosome alterations ( fig.…”