In part 1 of this series, I introduced a new phrase related to the COVID19 pandemic—cytokine storm. In this previous post, https://www.anoasisofhealing.com/the-covid-19-cytokine-storm-part-1/ I discussed:

  • What is a cytokine storm?
  • What are the different causes of a cytokine storm?

In this following post, I will connect the dots of the deadly cytokine storm found in COVID19 pneumonia to the cytokine storm in cancer. Does the cytokine storm from COVID19 cause cancer? No. But, the same cytokine storm process that wreaks havoc in COVID19 pneumonia also plays a major role in cancer.

“Make a habit of two things—to help, or at least, to do no harm.”

Hippocrates

An Oasis of Healing is a cancer healing center in Arizona. As Medical Director at An Oasis of Healing, we work daily to heal people with cancer. This is our #1 focus. That being said, cancer doesn’t exist in a bubble. We recognize and understand the connections that co-existing conditions, dis-ease, and self-inflicted damage have in the complications in the treatment and healing of people with cancer. Cytokine storm is one very important connection.

What is the relevance of the cytokine storm to cancer?

A cytokine storm does not have implications just in infections, such as in COVID19 pneumonia, previous SARS-Cov and MERS-CoV pandemics, Acute Respiratory Distress Syndrome (ARDS), and early sepsis [1] [2] [3], but there are significant evidence-based implications of cytokine storm or cytokine storm like responses in cancer. Specifically, the cytokine storm is implicated in:

  • Tumor Lysis Syndrome (TLS) [4] [5]
  • chemotherapy-induced metastatic spread of cancer [6] [7]
  • Stimulation of cancer growth [8] [9]

Cytokine storm or cytokine storm like response is implicated in the dangerous and life-threatening Tumor Lysis Syndrome. You did read the 2nd point correctly. One of the primary pillar treatments of cancer, chemotherapy, is a cause of the metastatic spread of the very cancer it is intended to treat with the aid of inflammatory cytokine storm signaling. Third, an understanding of the inflammatory signaling in a cytokine storm, TLS, and chemotherapy-induced metastatic spread of cancer implicates cytokine storm as a contributor to the rapid growth potential of some cancer types.

Tumor Lysis Syndrome (TLS)

Tumor Lysis Syndrome 5 is a self-inflicted complication that can trigger a cytokine storm. Tumor Lysis Syndrome is the result of  massive cancer cell die-off that is the result of treatment. It is the massive cancer cell die-off that triggers the overwhelming inflammatory response called—cytokine storm 4 5 [10] [11]. Cancer cell death is always a good thing, never doubt that, but it is the rapid, large, tumor lysis that triggers this unique inflammatory syndrome. Tumor Lysis Syndrome is more common in certain types of cancer i.e. lymphoma, leukemia multiple myeloma, and other rapidly growing tumor types [12] [13] [14] [15], but can be found in virtually any type of cancer with a large volume of tumor [16] [17]. In medical doctor speak, this is called a large tumor burden. Tumor lysis syndrome has no preference for any specific cause. Any treatment, whether “conventional” or “alternative” can cause this massive cancer cell die-off that can trigger a cytokine storm. Even the new conventional immunotherapy drugs can get in on the act and precipitate a cytokine storm [18] [19]. The unfortunate target of tumor lysis syndrome is the kidneys which can result in Acute Kidney Injury (AKI) and can even lead to kidney failure.

Chemotherapy-induced metastatic spread of cancer

“chemotherapy, despite decreasing tumor size, increases the risk of metastatic dissemination“

Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Science Translational Medicine. 2017.

Why use this quote? This quote connects the dots and pulls the back the curtain on the great Oz. This quote appropriately summarizes how the very therapy intended to treat cancer can cause the spread of cancer. But How? The short answer is a cytokine storm. Maximum tolerated chemotherapy, think high-dose chemotherapy, precipitates a cytokine storm that causes the metastatic spread of cancer 6 7 8 [20].

The exact mechanisms are well known and include:

  • Chemotherapy changes the tumor microenvironment (TME) 7 [21]
  • Chemotherapy promotes epithelial to mesenchymal transition (EMT) 7 [22]
  • Chemotherapy promotes physical cancer cell escape [23]
  • Chemotherapy recruits blood vessel and lymphatic vessels to the tumor microenvironment [24] [25]
  • Chemotherapy promotes immune system escape [26]
  • Chemotherapy increases Circulating Tumor Cells (CTC) [27]
  • Chemotherapy prepares a favorable environment for distant metastasis 6 7 [28]

 

Interestingly enough, low-dose chemotherapy does not appear to provide the same increased potential for metastasis as the high-dose or maximum tolerated chemotherapy [29] [30] approach. As is always the case, the dose is everything!

Cancer

Though no studies have shown that chemotherapy specifically induces increased cancer growth through a cytokine storm, the implication is there none the less. As highlighted above, it sure does cause it to spread. If that isn’t growth, not sure I know what the word means. It doesn’t take a double-blinded, randomized placebo-controlled trial to know that 1 + 1 = 2. What do I mean? Take triple-negative breast cancer for example. This type of cancer grows rapidly and is often poorly responsive to treatments. I have personally seen chemotherapy precipitate the rapid growth of these tumors. The assumption was always that chemoresistance was the underlying issue behind this finding, but with new studies highlighting the cytokine storm of chemotherapy, another explanation could be that the chemotherapy is precipitating a cytokine storm that promotes growth.

The implication is that an increase in inflammation that is consistent with a cytokine storm will cause an increase in the growth potential of cancer. One of the best growth index markers available is ki-67. Though studies have not directly linked chemotherapy to an increase in ki-67, there are a growing number of studies that have linked chemotherapy to increased growth 8 9. This appears to be in high-dose, maximum tolerated chemotherapy but not in the low-dose delivery of chemotherapy 6. So, yes to the pro-growth effects of high-dose chemotherapy, but unknown to an increase in ki-67. It would appear that an increase in growth would translate to an increase in ki-67, but sometimes that is where research leaves you. Remember, 1 + 1 = 2.

Beyond high-dose versus low-dose chemotherapy, the different dose-effect is also found in Interleukin 2 (IL-2) therapy. Studies clearly show that high-dose IL-2 in the treatment of melanoma and renal cell cancer is associated with a significant risk of cytokine storm [31] and as a result significant toxicities. As a result, very good immunotherapy may have limited use because of significant side effects; but of course, that is a great reason. As I have said previously, the dose is everything. It comes as no surprise that a low-dose of IL-2 doesn’t appear to trigger a pro-inflammatory cytokine storm like reaction compared to the high-dose IL-2. The right therapy is the result of the right dose at the right time. The wrong dose and/or the wrong time renders the right therapy the wrong therapy.  More will be discussed in high-dose versus low-dose chemotherapy in a future blogpost discussing the treatments of the cytokine storm.

In part 2 to this follow up post, I will discuss each point in more detail of exactly how chemotherapy is connected to metastasis through cytokine storm.

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[1] Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, Lei HY. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol. Feb 2005;75(2):185-94.

[2] Kim ES, Choe PG, Park WB, et al. Clinical Progression and Cytokine Profiles of Middle East Respiratory Syndrome Coronavirus Infection. J Korean Med Sci. 2016;31(11):1717–1725. doi:10.3346/jkms.2016.31.11.1717

[3] Chousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 2017 Jul;39(5):517-528. doi: 10.1007/s00281-017-0639-8

[4] Shimabukuro-Vornhagen, A., Gödel, P., Subklewe, M. et al. Cytokine release syndrome. j. immunotherapy cancer 6, 56 (2018). https://doi.org/10.1186/s40425-018-0343-9

[5] Howard SC, Jones DP, Pui C-H. The tumor lysis syndrome. N Engl J Med. 2011;364:1844–54.

[6] 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

[7] 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

[8] Gartung A, Yang J, Sukhatme VP, Bielenberg DR, Fernandes D, Chang J, Schmidt BA, Hwang SH, Zurakowski D, Huang S, Kieran MW, Hammock BD, Panigrahy D. Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor. Proceedings of the National Academy of Sciences Jan 2019, 116 (5) 1698-1703; DOI: 10.1073/pnas.1803999116

[9] Cui L, et al. Chemotherapy induces ovarian cancer cell repopulation through the caspase 3-mediated arachidonic acid metabolic pathway. Onco Targets Ther. 2017;10:5817–5826.

[10] Tonini G, Santini D, Vincenzi B, Borzomati D, Dicuonzo G, La Cesa A, et al. Oxaliplatin may induce cytokine-release syndrome in colorectal cancer patients. J Biol Regul Homeost Agents. 2002;16:105–109.

[11] Aue G, Njuguna N, Tian X, Soto S, Hughes T, Vire B, et al. Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia. Haematologica. 2009;94:1266–1273. doi: 10.3324/haematol.2009.005835.

[12] Belay Y, Yirdaw K, Enawgaw B. Tumor Lysis Syndrome in Patients with Hematological Malignancies. J Oncol. 2017;2017:9684909. doi:10.1155/2017/9684909

[13] Cairo M. S., Thompson S., Stern L., Sherman S. Incidence of treatment-related, laboratory and clinical tumor lysis syndrome. Blood. 2012;120(21),328.

[14] Krishnan G, D’Silva K, Al-Janadi A. Cetuximab-related tumor lysis syndrome in metastatic colon carcinoma. J Clin Oncol. 2008;26:2406–8.

[15] Godoy H, Kesterson JP, Lele S. Tumor lysis syndrome associated with carboplatin and paclitaxel in a woman with recurrent endometrial cancer. Int J Gynaecol Obstet. 2010;109:254.

[16] Noh GY, Choe DH, Kim CH, Lee JC. Fatal tumor lysis syndrome during radio-therapy for non-small-cell lung cancer. J Clin Oncol. 2008;26:6005–6.

[17] Joshita S, Yoshizawa K, Sano K, et al. A patient with advanced hepatocellular carcinoma treated with sorafenib tosylate showed massive tumor lysis with avoidance of tumor lysis syndrome. Intern Med. 2010;49:991–4.

[18] Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood. 1999;94.

[19] Rotz SJ, Leino D, Szabo S, Mangino JL, Turpin BK, Pressey JG. Severe cytokine release syndrome in a patient receiving PD-1-directed therapy. Pediatr Blood Cancer. 2017;64:e26642.

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

[21] Perelmuter VM, Tashireva LA, Savelieva OE, et al. Mechanisms behind prometastatic changes induced by neoadjuvant chemotherapy in the breast cancer microenvironment. Breast Cancer (Dove Med Press). 2019;11:209–219. Published 2019 Jul 5. doi:10.2147/BCTT.S175161

[22] Liu G, Chen Y, Qi F, Jia L, Lu XA, He T, Fu Y, Li L, Luo Y. Specific chemotherapeutic agents induce metastatic behaviour through stromal- and tumour-derived cytokine and angiogenic factor signalling. J Pathol. 2015 Oct;237(2):190-202. doi: 10.1002/path.4564. Epub 2015 Jun 15.

[23] 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

[24] 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.

[25] 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

[26] 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

[27] Camara O, Rengsberger M, Egbe A,  Koc A, Gajda M, Hammer U, Jörke C, Rabenstein C, Untc C, Pachmann K. The relevance of circulating epithelial tumor cells (CETC) for therapy monitoring during neoadjuvant (primary systemic) chemotherapy in breast cancer. Sept 2007;(18)9:1484–1492.

[28] Keklikoglou I, Cianciaruso C, Güç E, et al. Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models. Nat Cell Biol. 2019;21(2):190–202. doi:10.1038/s41556-018-0256-3

[29] Chan TS, Hsu CC, Pai VC, Liao WY, Huang SS, Tan KT, et al. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells. J Exp Med 2016;213:2967–88.

[30] Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;105:R15–24.

[31] Panelli MC, White R, Foster M, et al. Forecasting the cytokine storm following systemic interleukin (IL)-2 administration. J Transl Med. 2004;2(1):17. Published 2004 Jun 2. doi:10.1186/1479-5876-2-17

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