Researchers Investigate Link between Bacteria and Cancer of the Appendix

For many, the appendix is little more than a token of humankind’s evolutionary past, a vestigial organ that seems to contribute little to no function for the body.

Each year, however, it has been estimated that approximately one person per every 1 million people will develop what is known as pseudomyxoma peritonei (PMP), a rare type of appendiceal cancer. It has been estimated that most general practice doctors will see only one case of PMP each year, if any. Two support groups for PMP are: PMP Pals, and the ACPMP Research Foundation.

PMP most often originates in the appendix as a small growth, known as a polyp. This polyp eventually breaks through the wall of the appendix and disperses cancerous cells to the lining of the abdominal cavity, known as the peritoneum.

Unlike most cancers, PMP initially does not spread through the bloodstream or lymphatic system. Instead, a jellylike fluid known as mucin collects inside the abdomen, often but not always taking a long time to develop and cause symptoms.

There exists a great need for understanding the factors that lead to PMP tumor growth and the spread of PMP to other organs in the body.

Knowing this, and driven by a personal connection to PMP, Professor Emeritus Thomas J. McAvoy (Department of Chemical and Biomolecular Engineering, Institute for Systems Research, Fischell Department of Bioengineering) set out in 2004 with Dr. Armando Sardi, Medical Director for the Institute for Cancer Care at Mercy Medical Center in Baltimore, and the late Dr. Andre Dubois of the Uniformed Services University of Health Sciences (USUHS) in Bethesda to learn more about a possible link between bacteria and PMP.

In 2008, the trio teamed up with other Mercy and USUHS researchers to publish a paper on bacterial involvement in PMP in the Annals of Surgical Oncology – just four years after McAvoy lost his beloved wife Jessie to the orphan disease (see Publications on this website for all paper citations).

In the paper, the research group noted that H. pylori, a bacterium that can cause stomach cancer, and other bacteria were found in PMP tumors. Dr. Dubois hypothesized that pre- and post-operative antibiotic treatment could enhance the efficacy of the standard treatment for PMP, namely cytoreductive surgery to remove the mucinous tumor from the peritoneum plus heated intraperitoneal chemotherapy (HIPEC), a form of treatment performed after the surgery.

In 2009, Dubois and his lab director, the late Dr. Cristina Semino Mora, expanded the group’s research to study the β-catenin protein, and the group published results of the research in Clinical Cancer Research in 2013.

Normally, β-catenin resides in cell membranes and it helps cells adhere to one another. When β-catenin migrates inside cells, it becomes easier for cells to metastasize, and increased levels of intracellular β-catenin are often an indicator of cancer.

The β-catenin study compared 14 antibiotic treated patients to 34 not receiving antibiotics, and produced a comparison of bacterial densities in tumors from these two groups.

Incredibly, bacteria, including H. pylori, were detected in 83 percent of PMP tumors. In the more malignant form of PMP (PMCA – peritoneal mucinous carcinomatosis), patients treated with antibiotics had a significantly lower bacterial density and decreased β-catenin levels inside cells. Cell membrane β-catenin was significantly increased in all PMP patients receiving antibiotics, which indicates that the tendency for metastasis was decreased in patients who received antibiotics.

In 2007 Dr. Dubois recruited Dr. Traci Testerman, a microbiologist, to join the research group. Dr. Testerman is currently at the University of South Carolina and she is an expert in culturing bacteria. Dr. Testerman studied culturing bacteria from PMP tumor specimens, which is very difficult to do. She was successful in her work and has been able to culture about a dozen organisms from PMP specimens.

Dr.Testerman’s results for one interesting bacterium were published in Genome Announcements, in 2015.

In late 2008 Dr. Dubois recruited Dr. Scotty Merrell , to join our research group. Scotty is a microbiologist at USUHS. One of Dr. Merrell’s interests is the microbiome, which involves the microorganisms, especially bacteria, in a particular environment (including the body or a part of the body).

Dr. Merrell’s group analyzed tumor specimens from 11 PMP patients and sequenced a portion of a particular gene to profile the bacterial communities that were associated with the specimens. The microbiome results were published in Orphanet Journal of Rare Diseases in 2013.

Dr. Merrell took over for Dr. Dubois after his passing from mesothelioma in 2012.

In 2015 Dr. Jessica Metcalf, a microbiologist, was recruited by Dr. Sardi to join the research group. Dr. Metcalf is currently at Colorado State University, and she is associated with the American Gut Project (AGP) which is a diverse microbiome project. AGP participants submit a fecal sample for microbiome analysis through culturing. An AGP study has been initiated to assess any differences between the gut microbiomes of Dr. Sardi’s PMP patients and those of healthy people.

En masse, the research put forth by the group offers hope that, in addition to cytoreductive surgery with HIPEC, PMP patients might benefit from a novel co-treatment with antibiotics. Preliminary and encouraging survival results for using antibiotics are given in the Orphanet Journal of Rare Diseases publication.

Although the group’s research links bacteria and PMP, whether bacteria cause the disease or take advantage of it and the potential benefits of pre- and post-operative antibiotics have not yet been definitively determined. The research is ongoing and additional PMP patients are being treated with antibiotics to assess their benefit.

Detailed information about McAvoy’s personal journey to find a cure for PMP is featured in his book, Science Deepens Faith: Jessie’s Miracle, discussed on this website and available via Xulon Press and Amazon. In the book a detailed history of the PMP research from its initiation in 2004 through the beginning of 2016 is given. In the Research Updates section on this website  updates are given on a biannual basis from 1/2016 to the present.

Our research continues along three lines: animal and culturing research (Dr. Testerman), microbiome research (Dr. Merrell), and American Gut (AGP) research (Dr. Metcalf). In addition to her culturing research, Dr. Testerman has implanted PMP tumors into mice and studied their growth. We also began enrolling new patients in our pre- and post-operative antibiotics protocol (Dr. Sardi). Dr. McAvoy acts as research coordinator.