New Study Lays Groundwork for Potential New Anti-Cancer Therapy

Identification of a lymphatic endothelium origin may enable development of targeted therapies for angiomyolipoma and lymphangioleiomyomatosis, according to a new report in The American Journal of Pathology

Philadelphia, PA, June 8, 2016

Identifying the cell of origin is crucial to understanding how a tumor develops and metastasizes and for developing targeted therapies. Researchers have found evidence supporting a lymphatic endothelium origin for angiomyolipoma (AML) and lymphangioleiomyomatosis (LAM), two related tumors with previously unknown cellular origins. Furthermore, the newly identified lymphatic endothelial lineage shows translational potential for pharmaceutical treatment. Their findings are published in The American Journal of Pathology.

“As both AML and LAM are tightly linked processes, they are thought to be different manifestations of a common process,” explained lead investigator Lucia Nieto Schuger, MD, of the Department of Pathology at The University of Chicago. “As a result of our investigation of the cell of origin for an AML cell line derived from a LAM patient, we were able to suggest a potential novel origin for LAM mechanistically dependent upon TSC [tuberous sclerosis complex] inactivation as well.”

The researchers used an AML-derived cell line to determine whether restitution (re-expression) of the TSC2 protein would promote differentiation into the cell type from which AML arises. In this cell line and histological sections of AMLs, several embryonic lymphatic endothelial cell (LEC) markers consistent with LEC precursors were expressed. Upon TSC2 correction, AML cells matured immunophenotypically into adult LECs and showed functional attributes of this lineage. Such lymphatic mimicry observed in many cancers represents a curious enigma, but the molecular mechanisms for a ‘failed’ or ‘dysregulated’ lymphatic system are striking, opening the door for development of improved therapies.

Previous clinical trials with rapamycin, the only FDA-approved drug for treating LAM and AML, have been only partially successful. Combined therapies with rapamycin followed by surgery, in the case of AML, or addition of second drug, particularly in the case of LAM, are therefore the focus of much attention.

The investigators found that the lymphangiogenesis inhibitor norcantharidin halted the proliferation of both TSC2+ and TSC2- AML cells in vitro. Norcantharidin used in combination with rapamycin also produced promising preliminary results. “These studies showed an additive effect between rapamycin and norcantharidin, demonstrating preliminary effectiveness in repurposing an anti-lymphangiogenic drug as co-adjuvant therapy for rapamycin and thereby presenting as a potential new therapeutic approach for patients suffering from AML and most likely for patients suffering from LAM,” stated Dr. Schuger.

AMLs, the most common benign heterogeneous kidney tumors, are composed of blood vessels, smooth muscle cells, and fat cells featuring mutations in genes of the TSC cell growth pathway. Although most AMLs are benign, some tumors spread to local lymph nodes and may impair kidney function or ultimately lead to life-threatening retroperitoneal hemorrhage. These tumors frequently occur in patients suffering from LAM, a rare lung disease of borderline malignancy. The LAM nodules, which are indistinguishable from AML cells, tend to enlarge, proliferate, and cause cystic destruction of the lung leading to respiratory insufficiency.


Notes for editors
“Evidence Supporting a Lymphatic Endothelium Origin for Angiomyolipoma, a TSC2- Tumor Related to Lymphangioleiomyomatosis,” by Michael Yue, Gustavo Pacheco, Tao Cheng, Jefferine Li, Yitang Wang, Elizabeth P. Henske, and Lucia Schuger (doi: 10.1016/j.ajpath.2016.03.009). This article appears online in advance of The American Journal of Pathology, Volume 186, Issue 7 (July 2016), published by Elsevier.

Full text of this study is available to credentialed journalists upon request; contact Eileen Leahy at +1 732 238 3628 or Journalists wishing to interview the authors should contact John Easton, Senior Science Communication and Media Associate, at +1 773 795 5225,; or Ashley Heher, Assistant Director of the News Office, at +1 773 702 0025 or

This research was supported by National Institutes of Health Grant R01GM111116 (L.S.).

About The American Journal of Pathology
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.

The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology – close to 40,000 cites in 2014 – with an Impact Factor of 4.591 and Eigenfactor of 0.06689 according to the 2014 Journal Citation Reports®, Thomson Reuters, 2015, and an h-index of 217 according to the 2014 SCImago Journal and Country Rank.

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