Chemotherapy-induced metastasis: An unexpected foe?

By Yoskaly Lazo-Fernandez, PhD

Introduction

Evidence has accumulated recently indicating that common cancer therapies might stimulate metastasis in a significant number of cancer patients¹. In fact, neoadjuvant chemotherapy (NAC) drugs, which are administered preoperatively as a first line of treatment, have been associated with increased infiltration of endothelial progenitor cells and macrophages in primary tumors, resulting in higher angiogenesis and tumor regrowth². Mechanisms by which these cellular injury responses induce metastasis, both in preclinical in vivo models, and in human patients have been elucidated recently in two independent studies.

The tumor microenvironment of metastasis

In their excellent article, Karagiannis et al.³ relied heavily on the histological analysis and intravital-imaging functional assessment of a well-established marker for breast cancer metastasis, the tumor microenvironment of metastasis (TMEM)⁴. TMEMs are microanatomical assemblies of three different cell types inside tumors. These are: peritubular macrophages, tumor cells and endothelial cells. What is extraordinary about TMEMs is that their assembly seems to be indispensable for cancer cell intravasation and distant metastasis to occur⁵. Not surprisingly, the histopathological determination of TMEM scores in breast cancer patient biopsies has become a reliable prognosis marker associated with distant metastasis⁶.

VEGF165 was detected in immersion fixed frozen sections of human breast cancer tissue using 5 µg/mL Human VEGF165 Polyclonal Antibody (Catalog# AB-293-NA) overnight at 4℃. Tissue was stained (red) and counterstained with hematoxylin (blue). View our protocol for Chromogenic IHC Staining of Frozen Tissue Sections.

Mechanisms by which NAC induces breast cancer metastasis

Administration of NAC drugs such as paclitaxel or the doxorubicin/cyclophosphamide combination induced significant increases in TMEM scores in all of the 4 in vivo preclinical models of breast cancer that were tested in the project³. Moreover, these effects where functionally very relevant, as the same treatments stimulated all the molecular and functional markers associated with TMEM activity including:

1. The abundance of intra-tumoral perivascular macrophages, particularly those overexpressing the angiopoietin receptor TIE-2 and Vascular Endothelial Growth Factor (VEGF).
2. The intra-tumoral vascular permeability, with observable intervals of vessel leaking or bursting followed by tumor cell intravasation.
3. The plasmatic concentration of circulating tumor cells (CTC).
4. The incidence of lung metastasis and the number of metastasis per animal.
5. The expression of the mammalian enabled protein MENA, particularly of its tumor promoting isoform MENA^INV. Moreover, some of these results were replicated in samples from human breast cancer patients right after they received extensive NAC treatments.

The second paper by Chang et al.⁷ reported similar increases of TMEM activity in a breast cancer model after paclitaxel in vivo administration. In addition, this study showed that the pro-metastatic effects of chemotherapy extend to the metastatic host, non-cancerous, tissue. For example, in the metastatic lung, paclitaxel reduced the cytotoxic responses of T and NK cells and increased the presence of inflammatory monocytes, all of which stimulated the distant seeding and proliferation of cancer cells.

Significance

Overall these results regarding the pro-metastatic effects of paclitaxel and other chemotherapeutic drugs, are concerning and highly controversial. On the one hand, the curative and/or life-extending effects of these drugs in a number of cancer types, including a high percentage of breast cancer patients, needs to be defended. On the other, it wouldn’t be ethical to allow the subset of cancer patients that could be severely harmed by chemotherapy to go through the high costs and harsh side effects of these treatments. An open discussion on these issues has undoubtedly started, fueled by the very recent publication of several reviews in high impact journals^1,8–10.

Further research on this area is urgent, particularly on the identification of the molecular determinants of the curative vs. the pro-metastatic and potentially harmful response to chemotherapy in cancer patients. Such advances could allow the implementation of more personalized chemotherapeutic approaches. In the meantime, novel combination pharmacotherapies are being tested that could significantly alleviate this problem. For example, Karagiannis³ eliminated the pro-metastatic effects of paclitaxel by pretreating the mice with the TIE-2 inhibitor, currently undergoing clinical trials, rebastinib. Chang⁷ also attained encouraging results in the identification of the novel potential target, the transcription factor ATF3, whose potential pharmacological inhibition could also counteract the harmful pro-metastatic effects of chemo. It seems reasonable to predict that a much more personalized and effective set of treatment protocols for breast- and other types of cancer, is around the corner, we can hardly wait.

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Yoskaly Lazo Fernandez, PhD
Research Assistant Professor, The University of Kansas Medical Center
Dr. Lazo-Fernandez is interested in the application of novel immunotherapies for the treatment of cancer, particularly ovarian cancer.

References

1. Martin OA, Anderson RL, Narayan K, MacManus MP. Does the mobilization of circulating tumour cells during cancer therapy cause metastasis? Nature Reviews Clinical Oncology. 2017;14(1):32-44. doi:10.1038/nrclinonc.2016.128 .
2. Daenen L, Houthuijzen J, Cirkel G, Roodhart J, Shaked Y, Voest E. Treatment-induced host-mediated mechanisms reducing the efficacy of antitumor therapies. Oncogene. 2014;33(11):1341. doi:10.1038/onc.2013.94 .
   
3. Karagiannis GS, Pastoriza JM, Wang Y, Harney AS, Entenberg D, Pignatelli J, Sharma VP, Xue EA, Cheng E, Alfonso T, Jones JG, Anampa J, Rohan TE, Sparano JA, Condeelis JS, Oktay MH. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Science Translational Medicine. 2017;9(397):eaan0026. doi:10.1126/scitranslmed.aan0026 .
   
4. Oktay MH, Jones JG. TMEM: a novel breast cancer dissemination marker for the assessment of metastatic risk. Biomarkers in Medicine. 2015;9(2):81-84. doi:10.2217/bmm.14.104 .
   
5. Roussos ET, Wang Y, Wyckoff JB, Sellers RS, Wang W, Li J, Pollard JW, Gertler FB, Condeelis JS. Mena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors. Breast Cancer Research. 2010;12(6):1-16. doi:10.1186/bcr2784 .
   
6. Robinson BD, Sica GL, Liu Y-F, Rohan TE, Gertler FB, Condeelis JS, Jones JG. Tumor Microenvironment of Metastasis in Human Breast Carcinoma: A Potential Prognostic Marker Linked to Hematogenous Dissemination. Clinical Cancer Research. 2009;15(7):2433-2441. doi:10.1158/1078-0432.CCR-08-2179 .
   
7. Chang Y, Jalgaonkar SP, Middleton JD, Hai T. Stress-inducible gene Atf3 in the noncancer host cells contributes to chemotherapy-exacerbated breast cancer metastasis. Proceedings of the National Academy of Sciences. 2017;114(34):E7159-E7168. doi:10.1073/pnas.1700455114 .
   
8. Martin OA, Anderson RL. Editorial: Therapy-induced metastasis. Clinical & Experimental Metastasis. 2018;35(4):219-221. doi:10.1007/s10585-018-9914-x .
   
9. Karagiannis GS, Condeelis JS, Oktay MH. Chemotherapy-induced metastasis in breast cancer. Oncotarget. 2017;8(67):110733-110734. doi:10.18632/oncotarget.22717 .
   
10. Karagiannis GS, Condeelis JS, Oktay MH. Chemotherapy-induced metastasis: mechanisms and translational opportunities. Clinical & experimental metastasis. 2018;35(4):269-284. doi:10.1007/s10585-017-9870-x .