Thursday, August 17, 2017

Laying Hens and Epithelial Ovarian Cancer



Re Apoc-eclipse, stores around here are running out of bottled water and plastic gas cans, and gas stations in rural eastern Oregon are running low on gasoline. The internet is starting to bog down too (they are also predicting possible cell service outages on Monday due to the increase in users). Just look at this google map of traffic trying to get out of Portland. Sheesh, it's only 3:30pm on Thursday.


But that's not what I wanted to rant about. I wanted to post about my research project. I've been working on this project for three years now. I've cobbled together funding from several sources, and the entire thing has been run on a shoestring budget. This is my last free summer while in vet school, and I have to get everything wrapped up by the end of September, or at least as wrapped up as research ever gets. Which is really never if your project is exciting and you enjoy doing serendipitous discovery-driven science. 

For three years, I've been using laying hens to study ovarian cancer. Yeah, I know, that's pretty weird. Laying hens are not exactly the kind of laboratory animal you think of first. But they spontaneously develop tumors in the surface epithelium of their ovaries, and these tumors are microscopically and chemically similar to those that develop in women. Risk of this cancer in hens increases with age, just as it does in women. And the disease progression is very similar, such that advanced disease stages in hens are accompanied by metastases to other peritoneal organs and ascites, or fluid in the peritoneal cavity.

Why do hens get this type of cancer? Two easy reasons jump out: we have genetically selected commercial strains of hens to lay about an egg a day, which means an ovulation every 24 hours or so, and we manipulate the photoperiod of their environment to keep them in a continually active reproductive state. So after 24 months or so of this, they begin to get epithelial ovarian cancer. 

The big problem with this disease in women is that symptoms are non-specific and it is usually diagnosed late. The five-year survival rate of this disease following diagnosis, irrespective of treatment, is sadly low. Early detection is an elusive goal. But it is hard to get data on early expression of this disease in women. We can't just go around and sample ovaries of 20-year-old women to see what's going on. What are we looking for anyway?

When I learned that hens are a robust model for this disease, I thought, well, I know a little bit about chickens and maybe I can contribute something of value to this problem. Yeah, I know, it sounds crazy. Cancer research is big business with big-name players. Who the hell am I to get involved in that.

Well, I'll tell you. I am a scientist. I always have been. I am driven to learn about the world around me by my curiosity. I am not afraid to tackle new things because I know how to learn. The road to hell is paved with good intentions but I decided to head on down there with my ideas anyway.

Last summer, when I was looking at microscope slide after slide of hen ovaries, I realized that there was no detailed description of what a normal laying hen ovary looked like. Plenty of papers described gnarly cancerous ovaries. But where were the references for normal? What was the range of normal? I went to my collaborators and they all said, yeah, looks like you'll have to write that yourself. So I did. I hope to have a manuscript on the "histopathology of the normal laying hen ovary" submitted to an online journal in a couple of weeks. Submitted doesn't mean accepted but it's a necessary first step. I'm first author with three established names behind mine. It is a good paper and I will be extremely proud to see that one published (eventually....).

With that out of the way, I returned to my original plan: what does early expression of ovarian cancer look like in hens? Were there any proteins that I could measure in the blood of the hens that I could associate with disease before it forms grossly visible tumors? If so, was that protein also measurable in women?

While describing all those normal ovaries, I began to notice a few ovaries that seemed a bit abnormal. With more careful looking, my collaborators and I decided that we did in fact have a pathology in those ovaries that had not been described before. The pathology is associated with an increase in a specific type of immune cell, the heterophil, and an absence of small follicles. Heterophils in birds act like neutrophils in mammals: they are first responders to the site of tissue injury or a microbacterial invasions. They are usually associated with acute inflammation, and are mostly gone after about 24 hours when other immune cells take over. But there was no evidence that the heterophils in the abnormal ovaries were acting like that. So what the heck were they doing? 

I dived back into the cancer research literature, this time reading up on cancer and inflammation. A rich topic indeed. And I discovered that epithelial ovarian cancer in particular is associated with an increase in a key inflammatory protein that has also been associated with avian heterophils. So I ran a fancy test on the hen serum then statistics on the results and found that the hens with abnormal ovaries had elevated levels of this particular protein in their serum. So for our second manuscript, I'm proposing a link between early neoplastic changes, an increase in this inflammatory protein (it is secreted by cancerous epithelial cells), and the increase in heterophils and absence of small follicles in the affected hen ovaries. It's a link that has not been made before. 

I may not ever return to this project, although much more work can be done with it. I've learned a lot about laying hen anatomy (gross and micro) and reproduction, and I've learned a lot about ovarian cancer. Oh, and that rabbit-hole I dived into to learn about inflammation was time well spent. It is exciting to find things that nobody else has stumbled across yet. It is affirming to make even these small contributions to our body of scientific knowledge.