What you need to know:

High-dose chemotherapy, also known as maximum tolerated chemotherapy, induces a cytokine storm immune reaction that can lead to the metastatic spread of cancer. This cytokine storm induced metastasis via the following mechanisms: changes in the tumor microenvironment, promotion of epithelial to mesenchymal transition, cancer cell physical escape, recruitment of blood and lymphatic vessels to the tumor microenvironment, cancer cell immune escape, increase in circulating tumor cells, and in the preparation for metastatic spread through damage to distant, healthy sites in the body.

“Every new beginning comes from some other beginning’s end.”

― Lucius Annaeus Seneca

History is full of new beginnings. The science of medicine is full of new discoveries. It is the convergence of these 2 independent paths that result in what is called paradigm shifts. The Cambridge dictionary defines a paradigm shift as “a time when the usual and accepted way of doing and thinking about something changes completely”. In plain language, things get turned on their head. The result is a new way to think that provides new knowledge, new treatments, and new solutions where none previously existed. As the Roman Philosopher, Lucius Antaeus Seneca recognized, an end is not a negative, but is the positive of a new potential beginning.

This post is the next in line in the series on cytokine storm. Previously, I discussed what is a cytokine storm and explored the relationship between the cytokine storm and the COVID19 virus. The next post followed up with the connection between chemotherapy, cytokine storm, and cancer. This post will highlight more specific detail of how the chemotherapy induction of a cytokine storm can lead to the metastatic spread of cancer. This process is well described in scientific journals. It is not a theory. Conjecture need not apply. It is not even open for speculation. It is in fact, evidence-based. And so it begins…

Chemotherapy changes the tumor microenvironment (TME)

One of the hottest topics in cancer research today is the tumor microenvironment. No longer can a tumor be thought of as a solid ball of cells separated and isolated from healthy cells. The tumor microenvironment is an ever-changing environment that consists of cancer cells and healthy cells co-existing and interacting together. This microenvironment of the tumor consists of many different types of cells, cancer and non-cancer, including cancer cells, cancer-associated fibroblasts (CAF), Tumor-associated macrophages (TAMs), Natural Killer cells (NK cells), Tregulator cells (Treg), endothelial cells, mast cells, Tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSC), platelets, and the extra-cellular matrix (ECM) [1]. Chemotherapy recruits the immune cells (TAMs, TANs, Tregs…) to the local tumor microenvironment through immune signals called chemokines. Cancer then manipulates these recruited immune cells, which are intended to destroy cancer, to protect cancer.

Cancer manipulates the immune system in many different ways, but one way is through what is called Tumor-Associated Macrophage (TAM) type II (M2) polarization. What is polarization? Just think of a continuum with M2 macrophages on one pole and M1 macrophages on the opposite pole. This continuum of M1 versus M2 macrophages appears to be quite fluid with changes in the environment dictating the movement between poles. M2 macrophage polarization is the push of the continuum to the M2 pole because of the environment. Cancer creates an environment that favors M2 polarization. This M2 favorable environment includes:

  • Hypoxia (low oxygen) environment [2] [3]
  • Increased lactic acid production in the tumor microenvironment via aerobic glycolysis (Warburg effect) [4] [5]
  • Acidic pH in the tumor microenvironment [6] [7]
  • chemotherapy-induced cytokine storm inflammatory burst [8] [9]

M2 macrophages promote proliferation, tissue remodeling, immune regulation, angiogenesis… Though important in the non-cancer inflammatory healing process, this process is manipulated by cancer to promote it’s self-survival and spread. There are 2 types of Tumor-Associated Macrophages (TAMs). In the context of cancer, type I (M1) macrophages are anti-cancer and type II (M2) macrophages are pro-cancer. Outside of the context of cancer, these TAMs function to prevent infection and restore healing through the same inflammatory signaling. With the recruitment of the TAMs to the tumor microenvironment and associated stress induced by chemotherapy [10] [11], the TAMs become polarized to M2 macrophages [12]. The M2 macrophages increase additional recruitment of macrophages to infiltrate the tumor as Tumor-Infiltrating Macrophages (TIMs) which increases local immunosuppression and chemotherapy resistance which favors cancer growth and metastasis.[13] What an evil web chemotherapy creates.

Chemotherapy promotes epithelial to mesenchymal transition (EMT).

Epithelial to mesenchymal transition is simply cancer evolving from a stable, non-proliferative (non-growth), non-mobile epithelial cell type to an increased proliferative, increased mobile, increased invasive, and increased aggressive mesenchymal cell type for spread of cancer. Essentially, epithelial to mesenchymal transition is cancer moving from a state of limited activity to a state of hyperactivity. Hyperactive cells are much more capable to spread. Those with young kids in the house know this scenario quite well. Research has shown that high-dose, also known as maximum tolerated, chemotherapy induces epithelial to mesenchymal transition [14] [15] [16]. The Tumor-Associated Macrophages described above, play an important role in the epithelial to mesenchymal transition of cancer cells [17]. It is all connected.

Chemotherapy promotes physical cancer cell escape

 The pièce de résistance is that high-dose chemotherapy promotes physical cancer cell escape through the building of channels or portals called Tumor Microenvironment of Metastasis (TMEMs). Who comes up with these names? TMEMs are composed of  3 different cell types: a macrophage, a tumor cell, and an endothelial cell. Through the creation of these portals, TMEMs help cancer cells that have acquired epithelial to mesenchymal transition, escape from the primary tumor to move into circulation. This is a key step, though not rate-limiting, in the potential for cancer metastasis. It is important to note that approximately 90% of deaths from cancer are due to the metastatic spread of cancer. It is obvious that TMEMs would play a very important role in the 90% potential.

High dose chemotherapy has been shown to increase [18] [19]:

  • TMEM assembly
  • TMEM number
  • TMEM permeability
  • TMEM activity

It is through this increase in portal assembly, portal number, and portal activity that cancer cells spread. In contrast, low-dose chemotherapy has not been shown to do this 8.

Chemotherapy creates and recruits blood vessels and lymphatic vessels to the tumor microenvironment

Why is chemotherapy recruitment of blood vessels and lymphatic vessels to the tumor microenvironment even important? These are the superhighways for the potential transport of metastatic cancer throughout the body. The process that supports the growth of blood vessels in cancer is called angiogenesis and the process that supports lymphatic vessel growth is called lymphagenesis. Though angiogenesis and lymphagenesis are part of the normal physiologic function of the body, the process of cancer is quite irregular. Though this irregularity may seem to hurt cancer, it further supports its growth and spread potential.

Not only do the cancer cells stimulate the production of new blood and lymphatic vessels, cancer draws these new vessels into the tumor microenvironment [20] [21]. Cancer uses these superhighways for travel. Think of high-dose chemotherapy as an under-construction sign as the local/state government builds a new 6 lane super highway to handle projected growth. In the case of cancer, that is a 6 lane superhighway with the blood vessel growth and another 6 lane superhighway with lymphatic vessel growth. All these superhighways are created with the intention to handle increased growth. No wonder chemotherapy can shrink the primary tumor and cause the spread of cancer at the same time. Cancer draws the tools to itself that is necessary for it to survive, grow, and spread.

Chemotherapy promotes immune system escape

Not only does chemotherapy induce physical cancer cell escape, but it also induces cancer cell escape from the immune system. Chemotherapy recruits immune cells, particularly the Tumor-Associated Macrophages described above, to the tumor microenvironment that protects cancer and destroys immune cells that target cancer for destruction. The polarization of M2 macrophages in the tumor microenvironment destroys the recruited immune cells that infiltrate the tumor microenvironment that is designed to target and destroy cancer cells. Cancer manipulates the immune system to protect itself at the expense of the body.

How about another mechanism by which chemotherapy induces immune escape? High-dose chemotherapy up-regulates the expression of PD-L1 [22] [23] [24]. Elevated PD-L1 is associated with the progression of cancer with worse survival outcomes in these patients. This glycoprotein is a way that cancer can evade the immune cells destined to attack it. For all you Star Trek Trekkies out there, PD-L1 is like a modern-day Klingon cloaking device for cancer to hide from the immune system. Or for you non-Trekkies out there, just think of it as the means to become invisible to the immune system.

You also may have heard of PD-L1 and/or PD-1 in reference to the new immunotherapy drugs, such as keytruda and opdivo. These drugs block these signals enabling the immune system’s ability to see cancer. Essentially, these drugs de-cloak the cancer so that it can be seen and targeted for destruction. High-dose chemotherapy can induce the expression of PD-L1 to evade the immune system to promote the systemic spread of cancer. No wonder, chemotherapy can shrink the primary tumor only to promote the spread of cancer. Maybe, we should rethink this strategy?

Chemotherapy increases circulating tumor cells (CTC)

An increase in circulating tumor cells with high dose chemotherapy is proof of concept for the TMEM portals discussed above. Circulating tumor cells are not uncommon in cancer. There is a normal base-line of circulating tumor cells released from a primary tumor in cancer. Chemotherapy induces a massive increase in circulating tumor cells above that base-line. This is like a military invasion and assault by cancer, all initiated and directed by the very therapy intended to destroy cancer—chemotherapy. Studies have shown that high-dose chemotherapy significantly increases circulating tumor cells 6. In one study 26, paclitaxel increased circulating tumor cells by an average of 1,000 fold in the treatment of breast cancer in the neoadjuvant setting. A 1,000 fold increase! This study found up to a 10,000 fold increase in circulating tumor cells on the high end. The average was just 1,000 fold increase. Chemotherapy creates a new base-line for circulating tumor cells. Again, should we rethink this strategy? Should we rethink the mechanism of this strategy?

Chemotherapy promotes a favorable environment for metastasis

This is called the seed and soil theory [25]. It is important to remember that approximately 90% of deaths from cancer is from the metastatic spread of cancer to distant sites [26]. Chemotherapy damages and changes the remote, non-cancerous, potential tissue micro-environments, not just the cancer primary tumor microenvironment. The chemotherapy-induced damage at the distant non-cancer sites create a more hospitable environment for cancer cells to survive and thrive upon their arrival. This is called the “seed and soil” theory. The potential distant tissue microenvironment is also referred to as the “pre-metastatic niche” [27]. It is the niche in which pre-metastasis originates. In this case, the soil of the distant tissue microenvironment becomes favorable for seed implantation because of damage induced by chemotherapy. Many different chemotherapy drugs (paclitaxel, gemcitabine, cisplatin, and cyclophosphamide) have been shown to increase the spread of cancer 10 [28] [29] [30]. The authors of the study, Chemotherapy-Exacerbated Breast Cancer Metastasis: A Paradox Explainable by Dysregulated Adaptive-Response [31], concluded:

“Chemotherapy was also shown to increase breast cancer metastasis by increasing the escape of cancer cells (seeds) from the primary tumors and by creating a more favorable tissue environment (soil) at the distant site for cancer cells to seed and colonize.”

In prostate cancer, chemotherapy has been shown to improve the distant microenvironment for metastasis 28. One can only conclude that chemotherapy cultivates and prepares distant “soils” for the “seeds” of cancer to land, sprout, and grow. This is a potential harvest that nobody wants and everything should be done to avoid.

Should we rethink this strategy? I have asked this question several times. The answer is yes. The next posts will dive into the therapeutic approaches that help change strategy that is a part of the paradigm shift.

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[1] Peltanova, B., Raudenska, M. & Masarik, M. Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: a systematic review. Mol Cancer 18, 63 (2019) doi:10.1186/s12943-019-0983-5

[2] Park, J.E., Dutta, B., Tse, S.W. et al. Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift. Oncogene 38, 5158–5173 (2019). https://doi.org/10.1038/s41388-019-0782-x

[3] Zhang J, Cao J, Ma S, et al. Tumor hypoxia enhances Non-Small Cell Lung Cancer metastasis by selectively promoting macrophage M2 polarization through the activation of ERK signaling. Oncotarget. 2014;5(20):9664–9677. doi:10.18632/oncotarget.1856

[4] Colegio OR, Chu NQ, Szabo AL, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513(7519):559–563. doi:10.1038/nature13490

[5] Mu X, Shi W, Xu Y, et al. Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer. Cell Cycle. 2018;17(4):428–438. doi:10.1080/15384101.2018.1444305

[6] Huber V, Camisaschia C, Berzi A, Ferro A, Lugini L, Triulzi T, Tuccitto A, Tagliabue E, Castellia C, Rivoltinia L. Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation. Seminars in Cancer Biology. Apr 2017;43:74-89.

[7] El-Kenawi, A., Gatenbee, C., Robertson-Tessi, M. et al. Acidity promotes tumour progression by altering macrophage phenotype in prostate cancer. Br J Cancer 121, 556–566 (2019). https://doi.org/10.1038/s41416-019-0542-2

[8] Karagiannis GS, Condeelis JS, Oktay MH. Chemotherapy-Induced Metastasis: Molecular Mechanisms, Clinical Manifestations, Therapeutic Interventions. Cancer Res. 2019;79(18):4567–4576. doi:10.1158/0008-5472.CAN-19-1147.

[9] Filippou PS, Karagiannis GS. Cytokine storm during chemotherapy: a new companion diagnostic emerges? Oncotarget. 2020;11(3):213-215.

[10] Chang YS, Jalgaonkar SP, Middleton JD, Hai T. Stress-inducible gene Atf3 in the noncancer host cells contributes to chemotherapy-exacerbated breast cancer metastasis. Proc Natl Acad Sci U S A. 2017;114(34):E7159–E7168. doi:10.1073/pnas.1700455114.

[11] Wolford CC, McConoughey SJ, Jalgaonkar SP, et al. Transcription factor ATF3 links host adaptive response to breast cancer metastasis. J Clin Invest. 2013;123(7):2893–2906. doi:10.1172/JCI64410.

[12] Dijkgraaf EM, Heusinkveld M, Tummers B, Vogelpoel LTC, Goedemans R, Jha V, Nortier JWR, Welters MJP, Kroep JR, Burg S. Chemotherapy Alters Monocyte Differentiation to Favor Generation of Cancer-Supporting M2 Macrophages in the Tumor Microenvironment. Cancer Res. April 2013;(73)8:2480-2492; DOI: 10.1158/0008-5472.CAN-12-3542

[13] Sanchez LR, Lucia B, Entenberg D, Condeelis JS. The emerging roles of macrophages in cancer metastasis and response to chemotherapy. Journal of Leukocyte Biology. Feb 2019; doi:10.1002/jlb.mr0218-056rr

[14] Sun Y, Campisi J, Higano C, et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med. 2012;18(9):1359–1368. doi:10.1038/nm.2890

[15] Poh ME, Liam CK, Mun KS, et al. Epithelial-to-mesenchymal transition (EMT) to sarcoma in recurrent lung adenosquamous carcinoma following adjuvant chemotherapy. Thorac Cancer. 2019;10(9):1841–1845. doi:10.1111/1759-7714.13156

[16] Fana J, Zhengab D, Ronga L, Zhu J, Hong S, Li C, Xu Z, Cheng S, Zhang X. Targeting epithelial-mesenchymal transition: Metal organic network nano-complexes for preventing tumor metastasis. Biomaterials. Sept 2019;139:116-126.

[17] Kuwada, K., Kagawa, S., Yoshida, R. et al. The epithelial-to-mesenchymal transition induced by tumor-associated macrophages confers chemoresistance in peritoneally disseminated pancreatic cancer. J Exp Clin Cancer Res. 2018;37(307). https://doi.org/10.1186/s13046-018-0981-2

[18] Karagiannis GS, Condeelis JS, Oktay MH. Chemotherapy-induced metastasis: mechanisms and translational opportunities. Clin Exp Metastasis 2018.

[19] Karagiannis GS, Pastoriza JM, Wang Y, Harney AS, Entenberg D, Pignatelli J, Sharma VP, XUE EA, Cheng E, D’ALFONSO TM, 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. Jul 2017;(9)397. DOI: 10.1126/scitranslmed.aan0026

[20] Liu G, Chen Y, Qi F, Jia L, Lu XA, He T, et al. Specific chemotherapeutic agents induce metastatic behaviour through stromal- and tumour-derived cytokine and angiogenic factor signalling. J Pathol. 2015;237:190–202.

[21] Alishekevitz D, Gingis-Velitski S, Kaidar-Person O, et al. Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3. Cell Rep. 2016;17(5):1344–1356. doi:10.1016/j.celrep.2016.09.083

[22] Yang M, Liu P, Wang K, et al. Chemotherapy induces tumor immune evasion by upregulation of programmed cell death ligand 1 expression in bone marrow stromal cells. Mol Oncol. 2017;11(4):358–372. doi:10.1002/1878-0261.12032

[23] Derer A, Spiljar M, Bäumler M, et al. Chemoradiation Increases PD-L1 Expression in Certain Melanoma and Glioblastoma Cells. Front Immunol. 2016;7:610. Published 2016 Dec 22. doi:10.3389/fimmu.2016.00610

[24] Zhang P, Su DM, Liang M, Fu J. Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Molecular immunology. 2008;45:1470–1476.

[25] Langley RR, Fidler IJ. The seed and soil hypothesis revisited–the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer. 2011;128(11):2527–2535. doi:10.1002/ijc.26031

[26] Seyfried TN, Huysentruyt LC. On the origin of cancer metastasis. Crit Rev Oncog. 2013;18(1-2):43–73. doi:10.1615/critrevoncog.v18.i1-2.40

[27] Feng, W., Dean, D.C., Hornicek, F.J. et al. Exosomes promote pre-metastatic niche formation in ovarian cancer. Mol Cancer 18, 124 (2019). https://doi.org/10.1186/s12943-019-1049-4

[28] Daenen L.G., Roodhart J.M., van Amersfoort M., Dehnad M., Roessingh W., Ulfman L.H., Derksen P.W., Voest E.E. Chemotherapy enhances metastasis formation via VEGFR-1-expressing endothelial cells. Cancer Res. 2011;71:6976–6985. doi: 10.1158/0008-5472.CAN-11-0627

[29] Gingis-Velitski S., Loven D., Benayoun L., Munster M., Bril R., Voloshin T., Alishekevitz D., Bertolini F., Shaked Y. Host response to short-term, single-agent chemotherapy induces matrix metalloproteinase-9 expression and accelerates metastasis in mice. Cancer Res. 2011;71:6986–6996. doi: 10.1158/0008-5472.CAN-11-0629

[30] Park S.I., Liao J., Berry J.E., Li X., Koh A.J., Michalski M.E., Eber M.R., Soki F.N., Sadler D., Sud S., et al. Cyclophosphamide creates a receptive microenvironment for prostate cancer skeletal metastasis. Cancer Res. 2012;72:2522–2532. doi: 10.1158/0008-5472.CAN-11-2928.

[31] Middleton JD, Stover DG, Hai T. Chemotherapy-Exacerbated Breast Cancer Metastasis: A Paradox Explainable by Dysregulated Adaptive-Response. Int J Mol Sci. 2018;19(11):3333. Published 2018 Oct 26. doi:10.3390/ijms19113333

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