Elucidating chemical cues in primary metastasis

University Of Illinois At Chicago, Chicago IL

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Abstract

ABSTRACT Cancer is a complex disease and high-grade serous ovarian cancer (HGSOC) is the leading and most lethal gynecological malignancy. Currently, there are limited options for detecting HGSOC in early stages and there are no routine tests that can effectively discriminate samples of healthy women from those with HGSOC. Recent evidence strongly suggests that most cases of HGSOC begin with tumorigenesis in the fallopian tube epithelium (FTE), and then tumors migrate to the ovary interior during ovulation. This primary metastasis is poorly understood from a molecular driver standpoint; many cancers migrate to specific organs and tissues and it is difficult to pinpoint the origin. Frequently throughout nature the migration of cells or organisms is dictated by chemotaxis, or the exchange of chemicals. Therefore, due to the spatial nature of HGSOC as well as other cancers, we have developed a novel method of imaging mass spectrometry (IMS) that can detect chemicals that are exchanged between the FTE and the ovary. Our method has successfully identified several mass-to-charge ratios (m/z?s, which represent chemicals) that are uniquely expressed in a coculture condition when a coculture of the ovary incubated with tumorigenic FTE cells is compared to either a FTE cell culture alone or ovary alone. An example of the power of this method is exemplified by our preliminary data: the first chemical that was identified and validated in this system by IMS was the neurotransmitter norepinephrine (NE). The IMS method demonstrated that NE is released from the ovary only in the presence of tumorigenic FTE when compared to other cell line controls. These data allow us to contextualize the previously described role for this stress-related catecholamine. Previous work by other groups have shown that NE can increase angiogenesis, cell invasion, and chemotherapy resistance in ovarian cancer. Furthermore, previous work demonstrated that ovarian cancer patients taking beta-blockers (which block NE production) had longer overall survival rates compared to those not taking beta-blockers. Our preliminary data adds to these important results to demonstrate that the primary metastasis of ovarian cancer is mediated in part by chemicals and that these chemicals and their receptors could be used as new therapeutics or targets. In this proposal I will identify and expand our understanding of the chemistry mediating metastasis, which could ultimately provide important clues toward finding new approaches to control cancer metastasis and design preventative techniques.