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 deaths3-5.
Metastasis
occurs when tumor cells leave their original site and colonize a new area of
the body, such as the lungs, liver, or bones3-5. The current treatment
options for sarcoma—surgery, chemotherapy, and radiation—are not very effective
against metastases6,7. Only 10-25% of STS patients respond to
chemotherapy, leaving surgery as the best option for many6,7.
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 patients8-10. 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 therapy11,13. 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 death6,7.
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