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Original Principles

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

                                                                                                            —Hippocrates

I call this an original principle. Hippocrates is considered the father of western medicine. Quotes like the above make Hippocrates a thorn in the direction of conventional medicine today. In the time of Hippocrates, and up until recently, the patient was the only focus in the practice of medicine. The doctor alone was the advocate for the patient and the patient alone. Today, medicine is dealing with problems of advocacy confusion. Medicine today has become an advocate for health insurance companies, hospitals, Medicare, health care organizations, government… It seems physicians and medicine are advocates for everything but the patient.

When it comes to cancer treatment, we must follow Hippocrates’ original principle. We must first do no harm as we help and heal patients. Hippocrates implied that these two objectives are not mutually exclusive, but in fact, are simultaneous objectives. I agree with the premise here with Hippocrates. More, I believe that they can and must be achieved together. Hippocrates’ words guide and direct focus, objective, advocacy, and works for the patient, and nothing else. Unfortunately for patients, when it comes to many cancer treatments today, Hippocrates’ words are not a guide but a contradiction.

Take metastasis, for example. Metastasis in cancer is a critical progression step that affects prognosis—outcome potential for healing. Metastasis is the cause of 90% of estimated morbidity and mortality in cancer patients. Any cancer treatments that seek to follow the guiding words of Hippocrates must consider the implication of treatment and its effects on metastasis.

How does chemotherapy match with these words?

How does radiation match?

Surgery?

Of course, I am not saying that there is no place for these conventional medicine pillars, only that their use be consistent with Hippocrates contextual words—help, heal, and do no harm. The Hippocratic principle directs to a more holistic approach and uses these conventional therapies to help or heal and do no harm. This drive was and is the reason behind Integrative Oncology. Not simply to integrate treatments, but to integrate the objectives to help, heal, and do no harm. Unfortunately, because physicians have forgotten our past, lost our advocacy focus, don’t independently read, and because of limited understanding of the process of metastasis, the three pillars of conventional cancer treatments (full-dose chemotherapy, radiation, and surgery) have all been shown to cause metastasis. These three pillars can help eliminate cancer, but it cannot see they heal, and it is clear that harm is a regular occurrence.

The process of metastasis has clearly defined steps [1] [2] [3] [4]:

  • Mitochondrial damage
  • Altered cellular metabolism
  • Altered genetic expression
  • Disrupted cellular signaling
  • Proliferation
  • Hypoxia
  • Angiogenesis
  • Lymphagenesis
  • Acidic tumor microenvironment
  • Tumor microenvironment immune recruitment
  • Tumor microenvironment immune dysfunction
  • Tumor microenvironment immune suppression
  • Systemic immune suppression
  • Immune escape
  • Tumor escape
  • Intravasation
  • Dissemination
  • Hypoxic memory
  • Cultivation of pre-metastatic niche
  • Extravasation
  • Metastasis

It is not the sequence here that is important, but the almost simultaneous process of carcinogenesis to metastasis that is important.

Treatments like full-dose chemotherapy, one of the three pillars of conventional cancer treatment, increase metastasis by [5] [6] [7] [8] [9]:

 changes in the tumor microenvironment

  • epithelial to mesenchymal transition (makes cancer mobile)
  • cancer cell physical escape
  • cancer cell immune system escape
  • increase in circulating tumor cells
  • promotion of favorable distant environments (pre-metastatic niche) for metastasis

How does full-dose chemotherapy align with the original Hippocrates principle? These pro-metastatic effects of full-dose chemotherapy are inconsistent and incompatible with Hippocrates’ words to help, heal, and do no harm.

 Likewise, radiation, another of the three pillars of conventional cancer treatment, beyond an increase in local recurrence, increases the risk of metastasis through 7 [10] [11] [12]:

  • increase release of circulating tumor cells
  • increase in circulating tumor cells (CTC) recruitment to the original tumor site
  • increase systemic CTC
  • alters the tumor microenvironment
  • local immune system suppression
  • increases local invasiveness of the original tumor
  • damages healthy cells increasing their susceptibility to tumor spread and initiation

More, radiation treatment increases the formation of new secondary cancers. Worse, clinical trials have shown a latent time of 7-9 years from radiation exposure. This high-risk radiation exposure extends out to even 10-13 years. This extended risk is far beyond the five-year standard definition of cure. But, who really has the right to declare cure? Physicians or God?

How does radiation align with the original Hippocrates principle? These pro-metastatic effects of radiation are inconsistent with Hippocrates’ words to help, heal, and do no harm.

Finally, surgery, the third of the three original pillars, causes metastasis and local recurrence through [13] [14] [15] [16] [17]:

  • Increase in inflammation
  • pro-carcinogenic alteration in the tumor microenvironment
  • increase in growth signaling
  • increase in physical escape
  • increase in immune escape
  • Increase in local and systemic immune suppression
  • increase in dissemination and circulation of circulating tumor cells
  • Increase in circulating tumor cell migration
  • Increase in circulating tumor cell invasion

Like radiation and full-dose chemotherapy, surgery can increase local recurrence and metastasis.

One common connection between chemotherapy, radiation, and surgery in metastatic risk is the concept of oncotaxis. Throughout the years in the scientific literature, this has been referred to as surgical oncotaxis and inflammatory oncotaxis. Surgical oncotaxis and inflammatory oncotaxis are different but just two sides of the same coin. Surgery causes inflammation that can cause re-seeding for local recurrence and distant seeding for metastasis. But, full-dose chemotherapy, radiation, and surgery stimulate inflammation that triggers metastasis via cytokine storm (link). A 2013 article, Inflammatory oncotaxis in cholangiocarcinoma, says it perfect:

“Inflammatory oncotaxis is the term used to describe the phenomenon whereby mechanically injured tissues are predisposed to the development of metastases. Normal tissue injury elicits an inflammatory response, and it has been found that the microenvironment created is similar to that of the tumour microenvironment. Subsequently tumours have often been described as ‘wounds that do not heal’.” [18]

It is essential to understand that the often injured sites include the vascular endothelium. It is this site of injury that aids metastasis. And, it appears the vascular endothelium is the preferred site of damage from the SARS-CoV-2 spike protein. More to come later.

As you can see, the process of metastasis and the effects of treatment on metastasis are well researched but by no means exact or completely understood. Some basic facts are known to be critical to the process of metastasis. These include invasion, immune suppression, circulation of cancer cells, and preparation of the pre-metastatic niche. True science provides discovery which provides a new direction. So, there should be new discoveries to come.

They say that big things come in small packages. The big thing is cancer metastasis, and the small packages are platelets. Platelets and their involvement in the process of cancer metastasis are a relatively new discovery. When science is allowed to focus on science apolitically, it is incredible the new ideas and discoveries it can provide—novel concepts.

Platelets are critically involved in the process of metastasis. Platelets are generally known for their assistance in clotting, which is good. But, in cancer, platelets are co-opted, and function is adulterated to help promote the process of cancer, specifically metastasis. Cancer has a repetitive pattern of co-opting normal function to support its abnormal function, to the detriment of the rest of the body.

This backdrop of metastasis is highly relevant to SARS-CoV-2, spike proteins, and LPS induced metabolic endotoxemia. The SARS-CoV-2 spike protein and LPS metabolic endotoxemia both promote metastasis, which I will discuss the specific details in future posts. Again, this is a significant point because 90% percent of morbidity and mortality associated with cancer is the direct result of metastasis. Prevent metastasis, and you prevent 90% percent of the heartache and death associated with cancer. Yet, many current conventional cancer treatment strategies contribute to and cause metastasis (link to previous post). As a result, anything, including any treatment, that increases metastasis can be said to be counter to the Hippocratic words: help, heal without harm. It is very apparent that we are in a post-Hippocratic era of medicine.

Platelets

The historical claim to fame for platelets is blood homeostasis. In addition to clotting factors, platelets play the role of blood coagulation—blood clotting. When most people hear of blood clotting, negative thoughts come to mind, i.e. deep venous thrombosis (DVT) and pulmonary emboli (PE). Of course, these are serious problems and warrant the appropriate concern. However, blood clotting is not all harmful. Look at a bleeding paper cut to see the benefit of blood coagulation. This vital process would be lost without platelets, and bleeding out from paper cuts would be a common experience for all that handle paper. Can you imagine paper cuts as the #1 cause of mortality? Of course not. The focus here is not the blood homeostasis function of platelets, but the less-known role platelets play that is critical to the discussion of metastasis.

Platelets play six significant roles in metastasis. First, platelets help promote the vital blood supply growth to help meet the high metabolic demand of cancer—a process called angiogenesis [19]. Without angiogenesis, cancer lacks the blood supply to meet the increased metabolic demand so characteristic of cancer. Second, platelets surround cancer cells in what is called a platelet–cancer cell aggregate [20] [21] as they circulate throughout the body. This aggregate acts as a shield or buffer to protect against the sheer forces that would otherwise tear the circulating tumor cells apart as they travel systemically throughout the body [22]. This is just another example of how cancer uses normal processes of the body for its benefit at the expense of the body as a whole. Third, the platelet-cancer cell aggregate creates the same shield or buffer, but this time for protection against immune system attack [23]. Again, the repetitive concept of co-option. Specifically, platelets form a buffer around the circulating cancer cells that prevents natural killer cell-directed cytotoxic activity against these circulating invaders [24] [25]. Natural killer (NK) cells are key immune cells involved in hand-to-hand combat against cancer. One 2019 article, entitled Platelets, Thrombo-Inflammation, and Cancer: Collaborating With the Enemy, referred to this process of platelet cancer cell aggregate evasion from natural killer cell activity as “collaboration with the enemy” [26]. Not to be repetitive, it fits with the repeating theme of cancer co-option of normal function for the benefit of cancer at the detriment of the body as a whole. Interestingly on this third point, vitamin C has been shown to interrupt this platelet cancer cell aggregation to increase cancer cell susceptibility to NK cell cytotoxicity activity [27] [28] [29]. This effect of vitamin C can only be achieved through intravenous delivery. Fourth, platelets play a critical role in the adhesion of circulating tumor cells to the endothelium in distant sites to initiate the process of micrometastasis. A damaged endothelium acts as a landing site for platelet-cancer cell aggregate invasion. Micrometastasis is the formation of microscopic metastasis. Given time, micrometastasis will create the macrometastasis seen by all. Interestingly, micrometastasis can remain dormant (reference). Fifth, and the result of the first four, platelets increase the aggressive behavior of cancer [30]. There is nothing good that can come out of an increase in cancer aggression. Anecdotally, this is something we are seeing currently. Sixth, platelets help cultivate and prepare the distant tissue sites for invasion—metastasis. These sites are called pre-metastatic niches, and platelets play an active role in preparation 26 [31] [32]. They cultivate the soil. Platelets are like a farmer grooming the distant fields for the upcoming seeding. The result will be a growing season and a future harvest that only brings destruction. Last, platelets help to export the tumor microenvironment (TME) with the circulating platelet—cancer cell aggregate [33].

The TME is the new and evolving understanding of how a tumor interacts with the rest of the body. No longer is a tumor seen as a solid ball of cells isolated and walled off from the rest of the body. The TME is where normal cells directly interact with cancer cells. The TME is critical to the survival of a primary tumor. Platelets help make this TME portable, which improves the viability of circulating tumor cells for metastasis.

In conclusion, platelet hyperactivity increases the metastatic dissemination of cancer cells via 34:

  • Increase in angiogenesis
  • Increase in cancer cell intravasation
  • Increase survival of circulating tumor cells (CTCs)
  • Increase in epithelial to mesenchymal transition
  • Increase in CTC activation
  • Immune system escape
  • Increase in cancer cell extravasation
  • Systemic dissemination of the local tumor microenvironment
  • Prepares distant, target tissue for metastasis (seed and soil theory)

The result is that the hyperactivation of platelets poses a clear and present danger for cancer metastasis.

Sometimes, the word holistic can mean natural. But, in other cases, holistic can mean using a conventional therapy in a more holistic approach. This approach aligns more with the help and healing, without harm, consistent with the original principle, not the post-Hippocrates approach that currently permeates conventional medicine today.

In the next post, I will specifically bring the SARS-CoV-2 virus, with its associated spike proteins, and the LPS induced metabolic endotoxemia into this discussion involving platelets and reveal its potential impact on cancer and metastasis. It is the platelets that serve as the bridge.


[1] Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423-1437. doi:10.1038/nm.3394

[2] van Zijl F, Krupitza G, Mikulits W. Initial steps of metastasis: cell invasion and endothelial transmigration. Mutat Res. 2011;728(1-2):23-34. doi:10.1016/j.mrrev.2011.05.002

[3] Martin TA, Ye L, Sanders AJ, et al. Cancer Invasion and Metastasis: Molecular and Cellular Perspective. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

[4] Zhang Qingbei. Molecular mechanisms that mediate metastasis suppressor activity of NM23-H1. 2006. University of Kentucky Doctoral Dissertations. 410. https://uknowledge.uky.edu/gradschool_diss/410

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

[6] 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 Aug 22;114(34):E7159-E7168. doi: 10.1073/pnas.1700455114.

[7] Gunjal PM, Schneider G, Ismail AA, Kakar SS, Kucia M, Ratajczak MZ. Evidence for induction of a tumor metastasis-receptive microenvironment for ovarian cancer cells in bone marrow and other organs as an unwanted and underestimated side effect of chemotherapy/radiotherapy. J Ovarian Res. 2015 Mar 28;8:20. doi: 10.1186/s13048-015-0141-7.

[8] Ratajczak MZ, Jadczyk T, Schneider G, Kakar SS, Kucia M. Induction of a tumor-metastasis-receptive microenvironment as an unwanted and underestimated side effect of treatment by chemotherapy or radiotherapy. J Ovarian Res. 2013;6(1):95. Published 2013 Dec 27. doi:10.1186/1757-2215-6-95

[9] D’Alterio C, Scala S, Sozzi G, Roz L, Bertolini G. Paradoxical effects of chemotherapy on tumor relapse and metastasis promotion. Semin Cancer Biol. 2020 Feb;60:351-361. doi: 10.1016/j.semcancer.2019.08.019.

[10] Lee SY, Jeong EK, Ju MK, et al. Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation. Mol Cancer. 2017;16(1):10. doi:10.1186/s12943-016-0577-4

[11] Zhang C, Liang Z, Ma S, Liu X. Radiotherapy and Cytokine Storm: Risk and Mechanism. Front Oncol. 2021 May 20;11:670464. doi: 10.3389/fonc.2021.670464.

[12] Sofia Vala I, Martins LR, Imaizumi N, et al. Low doses of ionizing radiation promote tumor growth and metastasis by enhancing angiogenesis. PLoS One. 2010;5(6):e11222. Published 2010 Jun 21. doi:10.1371/journal.pone.0011222

[13] Market M, Tennakoon G, Auer RC. Postoperative Natural Killer Cell Dysfunction: The Prime Suspect in the Case of Metastasis Following Curative Cancer Surgery. International Journal of Molecular Sciences. 2021; 22(21):11378. https://doi.org/10.3390/ijms222111378

[14] Tohme S, Simmons RL, Tsung A. Surgery for Cancer: A Trigger for Metastases. Cancer Res. 2017;77(7):1548-1552. doi:10.1158/0008-5472.CAN-16-1536

[15] Hirai T, Matsumoto H, Yamashita K, Urakami A, Iki K, Yamamura M, Tsunoda T. Surgical oncotaxis–excessive surgical stress and postoperative complications contribute to enhancing tumor metastasis, resulting in a poor prognosis for cancer patients. Ann Thorac Cardiovasc Surg. 2005 Feb;11(1):4-6.

[16] Neeman E, Ben-Eliyahu S. Surgery and stress promote cancer metastasis: new outlooks on perioperative mediating mechanisms and immune involvement. Brain Behav Immun. 2013;30(Suppl):S32–40. doi: 10.1016/j.bbi.2012.03.006.

[17] O’Leary DP, O’Leary E, Foley N, Cotter TG, Wang JH, Redmond HP. Effects of surgery on the cancer stem cell niche. Eur J Surg Oncol. 2016;42(3):319–325. doi: 10.1016/j.ejso.2015.12.008.

[18] Hutchison CMA, Hameed K, Zaitoun A, Madhusudana S. Inflammatory oncotaxis in cholangiocarcinoma. Grand Rounds. June 2013;13:57–62. doi: 10.1102/1470-5206.2013.0011

[19] Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147(2):275-292.

[20] Boukerche H, Berthier-Vergnes O, Penin F, et al. Human melanoma cell lines differ in their capacity to release ADP and aggregate platelets. Br J Haematol. 1994;(87)4:763-772.

[21] Hu L, Lee M, Campbell W, Perez-Soler R, Karpatkin S. Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood. 2004;104(9):2746-2751.

[22] Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer. 2011;11(2):123-134.

[23] Palumbo JS, Talmage KE, Massari JV, et al. Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and-independent mechanisms. Blood.2007;110(1):133-141.

[24] Toliopoulos IK, Simos YV, Oikonomidis S, Karkabounas SC. Resveratrol diminishes platelet aggregation and increases susceptibility of K562 tumor cells to natural killer cells. Indian J Biochem Biophys. 2013 Feb;50(1):14-8.

[25] Haemmerle M, Stone RL, Menter DG, Afshar-Kharghan V, Sood AK. The Platelet Lifeline to Cancer: Challenges and Opportunities. Cancer Cell. 2018;33(6):965-983. doi:10.1016/j.ccell.2018.03.002

[26] Palacios-Acedo AL, Mège D, Crescence L, Dignat-George F, Dubois C, Panicot-Dubois L. Platelets, Thrombo-Inflammation, and Cancer: Collaborating With the Enemy. Front Immunol. 2019;10:1805. doi:10.3389/fimmu.2019.01805

[27] Toliopoulos IK, Simos YV, Daskalou TA, Verginadis II, Evangelou AM, Karkabounas SC. Inhibition of platelet aggregation and immunomodulation of NK lymphocytes by administration of ascorbic acid. Indian J Exp Biol. 2011 Dec;49(12):904-8.

[28] Mousavi S, Bereswill S, Heimesaat MM. Immunomodulatory and Antimicrobial Effects of Vitamin C. Eur J Microbiol Immunol (Bp). 2019;9(3):73-79. Published 2019 Aug 16. doi:10.1556/1886.2019.00016

[29] van Gorkom GNY, Klein Wolterink RGJ, Van Elssen CHMJ, Wieten L, Germeraad WTV, Bos GMJ. Influence of Vitamin C on Lymphocytes: An Overview. Antioxidants (Basel). 2018;7(3):41. doi:10.3390/antiox7030041

[30] LeBlanc R, Peyruchaud O. Metastasis: new functional implications of platelets and megakaryocytes. Blood. 2016;128(1):24-31.

[31] Kerr BA, McCabe NP, Feng W, Byzova TV. Platelets govern pre-metastatic tumor communication to bone. Oncogene. 2013 Sep 5;32(36):4319-24. doi: 10.1038/onc.2012.447.

[32] Schlesinger M. Role of platelets and platelet receptors in cancer metastasis. J Hematol Oncol. 2018;11(1):125. Published 2018 Oct 11. doi:10.1186/s13045-018-0669-2

[33] Obermann WMJ, Brockhaus K, Eble JA. Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment. Front Cell Dev Biol. 2021;9:674553. doi:10.3389/fcell.2021.674553