UPenn Scientists Are Investigating Better Treatments for Sarcoma Tumors

by Adrian Rivera-Reyes and Koreana Pak

Soft tissue sarcomas (STS) are rare cancers of the connective tissues, such as bone, muscle, fat, and blood vessels. Soft and elastic, sarcoma tumors can push against their surroundings as they grow silent and undetected. Residing in an arm, torso, or thigh, it can take years before a sarcoma begins to cause pain. By the time a patient presents their tumor to a doctor, amputation may be unavoidable¹.

In 2017, it is predicted that 12,390 Americans will be diagnosed with sarcoma, and approximately 5,000 patients will die from these tumors². But the vast majority of these patients aren’t dying from the first tumor in their arm or leg—the real danger is metastasis, which is responsible for more than 90% of cancer-related deaths^3-5.

Metastasis occurs when tumor cells leave their original site and colonize a new area of the body, such as the lungs, liver, or bones^3-5. The current treatment options for sarcoma—surgery, chemotherapy, and radiation—are not very effective against metastases^6,7. Only 10-25% of STS patients respond to chemotherapy, leaving surgery as the best option for many^6,7. However, tumor cells can spread to other parts of the body even in early stages of sarcoma, long before the first tumor is even noticed. By the time the tumor is surgically removed, metastases have usually developed in other parts of the body.

As a sarcoma tumor grows, it becomes increasingly starved of oxygen and nutrients. Under these conditions, cancer cells are driven to metastasize. Moreover, tumor hypoxia, or low oxygen levels, are an important predictor of metastasis and low survival in sarcoma patients^8-10. In other words, the more tumor hypoxia, the lower a patient’s chance of surviving.

But how does this actually work? How does hypoxia drive sarcoma cells out of a tumor and into other organs, such as the lungs? Surprisingly, UPenn scientists have found it has a lot to do with collagen¹¹!

Metastasizing tumor cells (pink) associated with
collagen (blue). Image taken by Koreana Pak.

Collagen is the most abundant protein in the human body, but you’ll know it best as the substance that makes your skin flexible and elastic¹². This elastic material has many uses, and you can find it in gelatin, marshmallows, surgical grafts—and hypoxic tumors. In STS tumors, the low oxygen levels cause collagen to form sticky, tangled fibers.  Sarcoma cells will actually hijack this disorganized collagen and use it as a “highway” over which they can migrate out of the tumor and into other organs¹¹.

If these hypoxic collagen “highways” were disrupted in patient tumors, cancer cells could be prevented from metastasizing. But how?

In an effort to make this therapy a reality, UPenn scientists used models of human sarcoma and metastasis in which they could disrupt collagen. By deleting the hypoxia factors HIF-1 and PLOD2, they could restore normal collagen in tumors, which reduced tumor metastasis. Excitingly, they also found that minoxidil, a drug usually used to treat hair-loss, also reduced tumor collagen and halted metastasis¹¹.

Whether minoxidil could be used for human patients is unclear; nevertheless, drugs that reduce hypoxic targets like PLOD2 could serve as promising anti-metastatic therapies.

In a follow up study, these scientists looked at another hypoxic factor, called HIF-2¹³. While related to HIF-1, this protein actually plays a very different role in sarcoma. Elimination of HIF1 is important because it reduces metastasis¹¹. But when it comes to primary sarcoma tumors, the expression of HIF-2 can help reduce cancer cell growth¹³.

Again using a model of human sarcoma, the authors found they could increase tumor size when they eliminated HIF-2. They also used a clinically approved drug, Vorinostat, to treat these tumors, and saw that HIF-2 increased and as a consequence the tumors to shrank¹³.

Sarcoma Treatment: Going Forward

The diversity of STS, which comprises about 50 different types¹, as well as the low incidence of cases, makes it very challenging to develop better treatments for sarcoma. Clinical trials often combine patients with different types of sarcomas into a single study, even though the trial may not be a good fit for all the patients. A more specific approach is needed to treat the different types of sarcomas.

Through their research on hypoxia in sarcoma, UPenn scientists hope to improve current treatments. Their observation that HIF-1 and HIF-2 play opposing roles in different cancers is of particular importance, because HIF inhibitors are already being developed for cancer therapy^11,13. Doctors can also use markers like HIF-2 to predict how well patients will respond to different treatments. For example, patients with tumors that have low levels of HIF-2 will respond well to treatments with Vorinostat. Unfortunately, such predictive markers are rare in STS, and the identification of additional markers should complement the development of new treatments.

Complementing standard chemotherapy with new sarcoma-specific therapies would greatly improve current treatment options. However, treating the primary tumor alone is not sufficient, as metastasis remains primarily responsible for patient death^6,7. For this reason, further study into HIF-1/PLOD2 and the role of collagen in metastasis is needed. Through the development of drugs like minoxidil, which target harmful tumor collagen, we see exciting potential for the future of sarcoma therapy and patient survival.

References

1. Cancer.Net Editorial Board. (2012, June 25). Sarcoma, Soft Tissue – Introduction. Retrieved on April 4, 2017 from: http://www.cancer.net/cancer-types/sarcoma-soft-tissue/introduction

2. The American Cancer Society medical and editorial content team. (2017, January 6). What Are the Key Statistics About Soft Tissue Sarcomas? Retrieved on April 4, 2017 from https://www.cancer.org/cancer/soft-tissue-sarcoma/about/key-statistics.html

3. Mehlen, P., & Puisieux, A. (2006). Metastasis: a question of life or death. Nature Reviews Cancer, 6, 449-458.

4. Monteiro, J. & Fodde, R. (2010). Cancer stemness and metastasis: therapeutic consequences and perspectives. European Journal of Cancer, 46 (7), 1198-1203.

5. Nguyen, D.X., Bos, P.D., & Massagué, J. (2009). Metastasis: from dissemination to organ-specific colonization. Nature Reviews Cancer, 9, 274-284.

6. Linch, M., Miah, A. B., Thway, K., Judson, I. R., & Benson, C. (2014). Systemic treatment of soft-tissue sarcoma-gold standard and novel therapies. Nat. Rev. Clin. Oncol. 11(4), 187-202.

7. Lorigan, P., Verweij, J., Papai, Z., Rodenhuis, S., Le Cesne, A., Leahy, M.G., Radford, J.A., Van Glabbeke, M.M., Kirkpatrick, A., Hogendoom, P.C., & Blay, J.Y. (2007). Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastaic soft tissue sarcoma: a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. Journal of Clinical Oncology 25 (21), 3144-3150.

8. Shintani, K., Matsumine, A., Kusuzaki, K., Matsubara, T., Santonaka, H., Wakabayashi, T., Hoki, Y., & Uchida, A. (2006). Expression of hypoxia-inducible factor (HIF)-1 alpha as a biomarker of outcome in soft-tissue sarcoma. Virchows Arch. 449 (6), 673-681. 

9. Nordsmark, M., Alsner, J., Keller, J., Nielsen, O.S., Jensen, O.M., Horsman, M.R., & Overgaard, J. (2001). Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations. Br. J. Cancer 84 (8), 1070-1075. 

10. Rajendran, J.G., Wilson, D.C., Conrad, E.U., Peterson, L.M., Bruckner, J.D., Rasey, J.S., Chin, L.K., Hofstrand, P.D., Grierson, J.R., Eary, J.F., & Krohn, K.A. (2003). [(18)F]FMISO and [(18)F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia, metabolism, and VEGF expression. Eur. J. Nucl. Med. Mol. Imaging, 30 (5), 695-704.

11. Eisinger-Mathason, T.S.K., Zhang, M., Qiu, Q., Skuli, N., Nakazawa, M..S., Karakasheva, T., Mucaj, V., Shay, J.E., Stangenberg, L., Sadri, N., Puré, E., Yoon, S.S., Kirsch, D.G., & Simon, M.C. (2013). Hypoxia dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discovery, 3 (10), 1190-1205.

12. What is collagen? Retrieved on April 4, 2017 from http://www.vitalproteins.com/what-is-collagen.

13. Nakazawa, M.S., Eisinger-Mathason, T.S., Sadri, N., Ochocki, J.D., Gade, T.P., Amin, R.K., & Simon, M.C. (2016). Epigenetic re-expression of HIF-2 alpha suppresses soft tissue sarcoma growth. Nature Communications, 7, 10539