In the 1950s/1960s, links between stress and tumor growth were found, but molecular pathways were discovered not until the 1970/80s. One publication critically transformed the field of scientific inquiry.

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van den Brenk HA, Stone MG, Kelly H, Sharpington C. Lowering of innate resistance of the lungs to the growth of blood-borne cancer cells in states of topical and systemic stress. Br J Cancer. 1976;33(1):60-78. PMID: 175820

The first author

Hendrick (Athos Sydney) van den Brenk was born on 22^nd June 1921 in Sydney, Australia (he died on the 21^st of August 1992). He qualified as Bachelor of Medicine & Bachelor of Surgery in 1944, and he received his Master of Science in 1954. After two years of practice as a general surgeon, he was consultant radiotherapy research officer at the Melbourne Cancer Institute from 1956 to 1967. Then, he was awarded a Fellowship in Cancer research, and he became honorary consultant physician at St Thomas’s Hospital, London, from 1967 to 1978, becoming the Foundation Richard Dimbleby Professor of Cancer Research at St Thomas’s Hospital Medical School from 1975 to 1978. On returning to Australia due to private reasons, he became senior medical officer on the Repatriation Committee from 1979 and senior medical officer of the Commonwealth Department of Veterans’ Affairs. He had an international reputation as a clinical radiotherapist, radiobiologist and experimental oncologist, and he published over 250 papers (1).

The starting point

Until 1976, there existed contrasting results concerning the influence of stress or stressful treatment on tumor growth with either tumor-inhibiting (2,3) or tumor-propagating effects (4-6). However, in all these studies the immune system was not investigated, and these experiments were carried out without a focus on molecular pathways that might inhibit or propagate tumor growth. Form these studies (4-6), van den Brenk and colleagues reasoned “systemic stress indirectly lowers an innate resistance of tissues to growth of cancer cells”. And he further wrote that, presumably, “these results from pharmacologically induced changes in the target tissue which are mediated via neuroendocrinal pathways.”

The discovery

They investigated rats given Walker (W256) tumor cells, prepared in single cell suspension, and injected intravenously. These cells soon colonized the lungs to form metastases. To simulate a stressful situation, they used several different methods: 1) injection of adrenergic drugs, 2) injection of phosphodiesterase inhibitors (that increase effects through cyclic AMP), 3) local x-irradiation of the thorax, 4) convulsive seizures induced by pentylenetetrazole, and 5) restraint stress. Of all stressful interventions, irradiation (moderate effects), injection of isoproterenol (β1/β2-agonist with strong effects), of aminophylline (phosphodiesterase inhibitor with weak effects), of isoproterenol plus aminophylline (strongest effects), induction of convulsive seizures (moderate effects), and restraint stress (moderate effects) increased cancer colony growth in the lungs. The effects of restraint stress-induced increase of tumor colonies were inhibited by adrenalectomy. Furthermore, they recognized that cyclic AMP has a center role in the propagating effects on tumor growth.

In their discussion, they excluded effects through the immune system on obscure theoretical reasons, which might have prevented the ‘Author of this Blog’ to use this particular publication as an important contribution to the field. However, since van den Brenk and colleagues identified the important molecular cAMP-β-adrenergic pathway, which has later been clearly linked to inhibitory immune cell function and increased tumor growth (7-10, and many more), this paper was a trigger to transform this field of scientific inquiry.

Neuroimmunomodulation also published papers on the link between cancer, the immune system, and neuroendocrine modulation (11-16 and more).

References

1. URL: https://livesonline.rcseng.ac.uk/client/en_GB/lives/search/ — enter “E008377” in the search field
2. Rashkis HA. Systemic stress as an inhibitor of experimental tumors in Swiss mice. Science. 1952;116(3007):169-171. PMID: 14950226.
3. Anderson MR. Variations in the rate of induction of chemical carcinogenesis according to differing psychological states in rats. Nature. 1964;204:55-56. PMID: 14240113.
4. Fisher B, Fisher ER. Experimental studies of factors influencing hepatic metastases. III. Effect of surgical trauma with special reference to liver injury. Ann Surg. 1959;150(4):731-744. PMID: 13823186
5. Fisher B, Fisher ER. Experimental studies of factors influencing hepatic metastases. XI. Effect of hepatic trauma in hypophysectomized animals. Proc Soc Exp Biol Med. 1962;109:62-64. PMID: 13893220.
6. Robinson KP, Hoppe E. The development of blood-borne metastases. Effect of local trauma and ischemia. Arch Surg. 1962 Nov; 85:720-4. PMID: 13974455.
7. Stefanski V, Ben-Eliyahu S. Social confrontation and tumor metastasis in rats: defeat and beta-adrenergic mechanisms. Physiol Behav. 1996;60(1):277-282. PMID: 8804676.
8. Shakhar G, Ben-Eliyahu S. In vivo beta-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats. J Immunol. 1998;160(7):3251-3258. PMID: 9531281.
9. Hodgson DM, Yirmiya R, Chiappelli F, Taylor AN. Intracerebral interleukin-1beta impairs response to tumor invasion: involvement of adrenal catecholamines. Brain Res. 1999;816(1):200-208. PMID: 9878736.
10. Kalinichenko VV, Mokyr MB, Graf LH Jr, Cohen RL, Chambers DA. Norepinephrine-mediated inhibition of antitumor cytotoxic T lymphocyte generation involves a beta-adrenergic receptor mechanism and decreased TNF-alpha gene expression. J Immunol. 1999;163(5):2492-2499. PMID: 10452985.
11. Blom JM, Tamarkin L, Shiber JR, Nelson RJ. Learned immunosuppression is associated with an increased risk of chemically-induced tumors. Neuroimmunomodulation. 1995;2(2):92-99. PMID: 8521145.
12. Ben-Eliyahu S, Shakhar G, Page GG, Stefanski V, Shakhar K. Suppression of NK cell activity and of resistance to metastasis by stress: a role for adrenal catecholamines and beta-adrenoceptors. Neuroimmunomodulation. 2000;8(3):154-64. PMID: 11124582.
13. Shavit Y, Ben-Eliyahu S, Zeidel A, Beilin B. Effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats. Dose and timing study. Neuroimmunomodulation. 2004;11(4):255-260. PMID: 15249732.
14. ThyagaRajan S, Tran L, Molinaro CA, Gridley DS, Felten DL, Bellinger DL. Prevention of Mammary Tumor Development through Neuroimmunomodulation in the Spleen and Lymph Nodes of Old Female Sprague-Dawley Rats by L-Deprenyl. Neuroimmunomodulation. 2013;20(3):141-151. PMID: 23445569.
15. Alves GJ, Palermo-Neto J. Odor cues released by Ehrlich tumor-bearing mice are aversive and induce psychological stress. Neuroimmunomodulation. 2015;22(3):121-129. PMID: 24714518.
16. Anastassis I, Konsman JP. Causal Histories of Psychological Factors and Cancer: From Psychosomatic Medicine to Neuroimmunomodulation. Neuroimmunomodulation. 2024;31(1):143-156. PMID: 38934151.

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