Cancer: Evolution, ovulation and cancer
- National Centre for Biological Sciences, India
- National Institute of Immunology, India
Cancer of the ovaries is difficult to detect early, hard to treat, and its origins are still controversial. Now, in eLife, Jianjun Sun and Allan Spradling of the Carnegie Institution for Science report new data on an evolutionarily conserved pathway for the regulation of ovarian function in the fruit fly (Drosophila melanogaster), which could advance our understanding of ovarian cancer in humans (Sun and Spradling, 2013).
As with breast cancer, a woman's risk of developing ovarian cancer is increased if she inherits mutant forms of the genes BRCA1 and/or BRCA2. Some women with these mutations choose to have surgery to reduce their cancer risk (Berns and Bowtell, 2012), and studying tissues from these patients has increased our understanding of how the disease progresses. These and other studies have classified ovarian cancers into distinct types, and have also provided cell lines that can be used to study the disease at the molecular and cellular level (Levanon et al., 2010).
Some such studies suggest that cancers with an apparent ovarian origin—particularly high grade serous ovarian cancer—may in fact be cancers of the secretory epithelial cells of the fallopian tube. However, there is evidence that these cells may have an indirect role in some ovarian cancers too; simply tying off, or ligating, the fallopian tubes, which convey eggs from the ovaries to the uterus, decreases the incidence of ovarian cancer (Cibula et al., 2011). Moreover, there is other evidence for a link between ovarian cancer and the regulation of ovulation (Purdie et al., 2003). Although the major hormonal cues for ovulation are well characterized, the role of secretions from epithelial cells lining the fallopian tube in ovulation is poorly understood. However, if these pathways and molecules are conserved between species, the work of Sun and Spradling in Drosophila could allow us to make significant headway in understanding the secretory regulation of ovulation in mammals, and possibly shed new light on the genesis of ovarian cancers.
In both flies and mammals, ovulation usually results in the release of just one egg cell per cycle. In Drosophila, muscle contractions move the egg through the oviduct, where it can be fertilized by sperm stored in the spermathecae, before moving on to the uterus and finally being deposited from the vulva (Figure 1; Middleton et al., 2006). The work of Sun and Spradling builds on their previous research into the development of secretory glands in other parts of the female reproductive system (Allen and Spradling, 2008; Sun and Spradling, 2012). These studies identified the regulatory protein lozenge, which is a member of an evolutionarily conserved family of proteins called Runx, as an important player in secretory system development. And indeed, other members of the Runx family have been implicated in many ovarian cancers (Nevadunsky et al., 2009; Li et al., 2012; Keita et al., 2013).
Figure 1
The Drosophila female reproductive tract (figure adapted from Middleton et al., 2006). The mature egg is transported through the oviduct during ovulation and is fertilized by sperm stored in the spermathecae and seminal receptacle (the latter is not shown). The spermathecae and the accessory glands (parovaria) are the major secretory components of the female reproductive system. Sun and Spradling (2013) show that glandular secretions from these structures regulate ovulation and promote sperm storage. The innervation of muscles is shown in magenta. Scale bar: ∼250 μm.
IMAGE: Middleton et al. (2006).
Sun and Spradling's experiments now tease apart the multiple roles of the secretory glands to home in on those aspects relevant to sperm storage and ovulation. They do this in two ways. First, they alter the number of secretory cells in the reproductive tract and show that there are adverse consequences for sperm storage and sperm health, as well as for ovulation. In fruit flies, sperm are stored inside the spermathecae and the seminal receptacle within a few hours of mating. Sun and Spradling find that reducing the number of secretory cells (to fewer than 25) prevents the accumulation of sperm in the spermathecae but not in the seminal receptacle, suggesting that distinct mechanisms target and/or retain sperm in each location. However, even sperm that do accumulate in the receptacle aggregate abnormally, showing that secretions are also essential for the health of the stored sperm.
When Sun and Spradling modulate well-known ‘canonical' molecular pathways controlling secretion in these cells, sperm storage in the spermathecae is reduced. However, abolishing these canonical secretory pathways does not affect ovulation, even though a reduction in the number of secretory cells does; this suggests that the effect of altering secretory cell number on ovulation is likely to be mediated by one or more secretions through non-canonical pathways.
These findings raise important questions about our understanding of ovarian function and cancer. Does the number and/or secretory ability of fallopian tube epithelial cells correlate with either ovulatory capacity or the ability of tubal epithelium to bind and retain sperm, and could this explain some types of infertility? Might the secretory ability of cells within the female reproductive system be linked to their reported high propensity to DNA damage, and so directly mediate their contribution to ovarian cancer? Also, if the number of secretory cells and/or the integrity of non-canonical secretory pathways are regulators of ovulation, abnormalities in these may contribute to abnormal ovulation, which could, in turn, influence the likelihood of cancer.
Consistent with an indirect role for secretory cells in some ovarian cancers, it is noteworthy that members of the Runx family of gene regulatory proteins, familiar figures in ovarian cancers, are reported to regulate secretion (Little et al., 2012). Such a possibility would connect elegantly with the reduced frequency of ovarian cancers upon fallopian tube ligation. But which genes and proteins control these secretory pathways? There are now enough genetic and molecular tools available—in both fruit fly and mammalian systems—to make identifying these components a tractable endeavor. Isolating secretions from mammalian fallopian tubes and examining their effects on Drosophila ovulation could be a fruitful exercise, as could genetic approaches that screen directly for ovulation defects. The work of Sun and Spradling thus opens up new avenues for the genetic and molecular analysis of the properties and functions of secretory cells in the reproductive tract, and their potential role in evolutionarily conserved aspects of carcinogenesis.
References
-
Underlying mechanisms of ovarian cancer risk reduction after tubal ligationActa Obstet Gynecol Scand 90:559–563.https://doi.org/10.1111/j.1600-0412.2011.01114.x
-
Ovulation and risk of epithelial ovarian cancerInt J Cancer 104:228–232.https://doi.org/10.1002/ijc.10927
Article and author information
Author details
Publication history
Copyright
© 2013, VijayRaghavan and Rath
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 972
- views
-
- 69
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Cancer: Evolution, ovulation and cancer
eLife 2:e00729.
https://doi.org/10.7554/eLife.00729
Further reading
-
- Cell Biology
- Computational and Systems Biology
Induced pluripotent stem cell (iPSC) technology is revolutionizing cell biology. However, the variability between individual iPSC lines and the lack of efficient technology to comprehensively characterize iPSC-derived cell types hinder its adoption in routine preclinical screening settings. To facilitate the validation of iPSC-derived cell culture composition, we have implemented an imaging assay based on cell painting and convolutional neural networks to recognize cell types in dense and mixed cultures with high fidelity. We have benchmarked our approach using pure and mixed cultures of neuroblastoma and astrocytoma cell lines and attained a classification accuracy above 96%. Through iterative data erosion, we found that inputs containing the nuclear region of interest and its close environment, allow achieving equally high classification accuracy as inputs containing the whole cell for semi-confluent cultures and preserved prediction accuracy even in very dense cultures. We then applied this regionally restricted cell profiling approach to evaluate the differentiation status of iPSC-derived neural cultures, by determining the ratio of postmitotic neurons and neural progenitors. We found that the cell-based prediction significantly outperformed an approach in which the population-level time in culture was used as a classification criterion (96% vs 86%, respectively). In mixed iPSC-derived neuronal cultures, microglia could be unequivocally discriminated from neurons, regardless of their reactivity state, and a tiered strategy allowed for further distinguishing activated from non-activated cell states, albeit with lower accuracy. Thus, morphological single-cell profiling provides a means to quantify cell composition in complex mixed neural cultures and holds promise for use in the quality control of iPSC-derived cell culture models.
-
- Cell Biology
Collagen-I fibrillogenesis is crucial to health and development, where dysregulation is a hallmark of fibroproliferative diseases. Here, we show that collagen-I fibril assembly required a functional endocytic system that recycles collagen-I to assemble new fibrils. Endogenous collagen production was not required for fibrillogenesis if exogenous collagen was available, but the circadian-regulated vacuolar protein sorting (VPS) 33b and collagen-binding integrin α11 subunit were crucial to fibrillogenesis. Cells lacking VPS33B secrete soluble collagen-I protomers but were deficient in fibril formation, thus secretion and assembly are separately controlled. Overexpression of VPS33B led to loss of fibril rhythmicity and overabundance of fibrils, which was mediated through integrin α11β1. Endocytic recycling of collagen-I was enhanced in human fibroblasts isolated from idiopathic pulmonary fibrosis, where VPS33B and integrin α11 subunit were overexpressed at the fibrogenic front; this correlation between VPS33B, integrin α11 subunit, and abnormal collagen deposition was also observed in samples from patients with chronic skin wounds. In conclusion, our study showed that circadian-regulated endocytic recycling is central to homeostatic assembly of collagen fibrils and is disrupted in diseases.
