“What’s the Bladder? A Look into Bladder Cancer and the Tumor Suppressor Gene RhoGD12”

PattyP31
BI 490 Senior Seminar

Secondary News Article
Bladder Cancer; Endothelin axis is a target of the lung metastasis Suppressor Gene RhoGD12. (2005, October 7). NewsRx.com, p. 72.

Primary Research Article
Titus, B., Frierson, H.F., Conaway, M., Ching, K., Guise, T., Chirgwin, J., Hampton, G., Theodorescu, D. (2005). Endothelin Axis Is a Target of the Lung Metastasis Suppressor Gene Rho GD12. Clinical Cancer Research 65, (16). Retrieved February 11, 2008, from https://mail2.pmc.edu/exchweb/bin/redir.asp?URL=http://cancerres.aacrjournals.org/cgi/reprint/65/16/7320.

Articles That Cited Primary Article

Wu, Y., McRoberts, K., Frierson, H.F., Berr, S.S., Conaway, M., & Theodorescu, D. (2007). Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia. Oncogene, 26, Retrieved February 11, 2008,from http://www.nature.com/onc/journal/v26/n5/abs/1209835a.html.

Schunke, D., Span, P., Ronneburg, H., Dittmer, A., Vetter, M., & others (2007). Cyclooxygenase-2 Is a Target Gene of Rho GDP Dissociation Inhibitor in Breast Cancer Cells. Cancer Research, 67, Retrieved February 11, 2008,from http://cancerres.aacrjournals.org/cgi/content/abstract/67/22/10694.

Havaleshko, D.M., Cho, H.J., Conaway, M., Owens, C.R., Lee, J.K., Theodorescu, D., & Hampton, G. (2007). Prediction of drug combination chemosensitivity in human bladder cancer. Molecular Cancer Therapeutics, 6, Retrieved February 11, 2008,from http://mct.aacrjournals.org/cgi/content/abstract/6/2/578.

In a 2005 Drug week article a novel discovery linking bladder cancer and fatal metastatic lung cancer was made. The study originally published in the Cancer Research Journal by Titus and colleagues noted that patients with late stage bladder cancer relapsed with fatal lung cancer due to the spread of the cancer (metastasis). This may be connected to the endothelin axis and the tumor suppressor gene (whose loss of function affects cell division and growth) RhoGD12. Both the secondary Drug Week article and the primary article discussed the possible clinical applications of an endothelin (ET-1) inhibitor and its role in the metastasis into the lungs.

Before conducting the study it was hypothesized that the endothelin axis played a role in lung metastasis tumor suppressor gene RhoGD12 in late stage bladder cancer patients. According to recent statistics half of patients with late stage bladder cancer relapse with metastatic lung disease. Scientists knew that this was due to an inhibition of tumor suppressor genes and an increase in mutations which contribute to the “metastatic cascade” (Titus 7320). This led to the thought that the metastatic lung disease is associated with decreased expression of the tumor suppressor gene RhoGD12 because of its relationship with ET-1. In addition, ET-1 is also known to encourage cell division and growth especially angiogenesis (growth of blood vessels from pre-existing blood vessels) in lungs. Researchers also knew that a new drug therapy could be produced if the metastatic cascade could be interrupted and prevent metastasis; due to the fact that those patients with localized cancer have the greatest risk of metastatic disease because cancer cells may have already spread to other organs. However, the study was primed specifically to study late stage bladder cancer patients.

In order to discover the relationship between RhoGD12 and ET-1 researchers analyzed human tumor cells and the DNA changes that occur on the genetic level. Using DNA microarrays and RNA isolation researchers studied both non-metastatic and metastatic bladder cancer cells. Another component of the study was testing the role of ET-1 in cancer metastasis by giving a group of mice an ET-1 suppressor called atresentan in their drinking water for twelve weeks and observing the spread of cancer cells into the lungs. The findings were astounding.

The DNA microarrays found that there were many genes not being expressed, including RhoGD12 which functions as a suppressor of lung metastasis. Therefore, in the tested human bladder cells, as metastasis increased, RhoGD12 expression decreased. It was reasoned that the mechanism that controls rhoGD12 was controlled by genes downstream. The strongest downstream mRNA (which holds codons that make proteins) was ET-1. This showed that RhoGD12 affects the levels of ET-1. Although there was no direct statistical findings that would say that ET-1 is responsible for cell growth the administering of atresentan proved that its inhibition significantly lowered metastatic lung cancer in living cells.

In my opinion, the secondary article mirrors the primary almost exactly. I did not find the secondary article to be helpful in understanding the study or its findings. The secondary article merely spit out some quotes from the primary article and used its words to “summarize” itself. It seemed like a circular definition and would not recommend that anyone looking to do further research to read this article because the primary article was longer but more comprehensive, thorough and simpler than the secondary article. On the other hand, the secondary article did keep its summary concise despite using quotations from the primary article; somehow it was able to highlight the most important aspects of the study. It emphasized the Endothelin (ET-1) ligand role in cancer metastasis from the bladder to the lungs and the role of RhoGD12 in the body normally and its contribution to cancer formation. If I had to choose, I would choose the primary article over the secondary article. I do not trust an article made up of quotations from the original article. I might as well have the original article to refer to if that was the case. Despite some obvious differences there are some similarities between the two articles. Both emphasized the Et-1 ligand and its normal role as well as its role in cancer metastasis. It was also clear that RhoGD12 was one of the focal points of the articles and that suppression of the ET-1 ligand was like re-expressing the tumor suppressor gene RhoGD12 in the cancerous cells. Although both did not have exactly the same information what can be easily grasped from the articles is that this finding is crucial to new drug treatments because it may slow the process of metastasis in late stage bladder cancer patients; specifically into the lungs. I feel I have grasped the material but wonder if this finding is just prolonging the inevitable. The suppression of the ET-1 ligand does not stop the metastasis completely. I imagine that this would quickly turn into a bioethics debate on whether or not keeping someone who is headed for ill-fate due to late stage cancer then why would we want to keep them alive and prolong their suffering?



Questions:
1. In the primary article, the phrase “This finding is particularly relevant because it suggests that RhoGD12 may block paracrine tumor-host crosstalk in distant organs such as the lung, where metastasis occurs” was used (p.7324). Is “crosstalk” referring to the interaction between the lungs and other organs that are associated with the paracrine system?
2. Are there any other cases of cancer that tend to spread to a specific organ; similar to the bladder cancer discussed here that metastasizes to the lungs?
3. It was mentioned that the endothelian ligand has significant effects on bone cells and lung cells, which are two “important sites of bladder cancer metastasis” (p. 7326). Why is it that the lung is the only organ being discussed if skeletal cells are also affected by this type of bladder cancer?
4. Are there repercussions to inhibiting the ET-1 ligand? Could there be an imbalance caused by the future drug treatment?