“You are a fully embodied being who has never been separated from other biological beings both inside and outside your body.”

Timothy Morton. Being Ecological, Chapter 4, p. 156.

Physicians and medical researchers tend to analyze human disease and even normal physiological mechanisms detached from general biological processes. We often forget that a human organism is in itself an ecosystem and part of larger ecosystems. The interactions of colonizing organisms and human pathological processes are not usually seen in the context of systems and interactions of other organisms within larger environments. This disregard for general biological mechanisms in studying human disease have hindered the understanding of the biology of pathological processes affecting the human body. This is reflected by the naming of diseases often depicted without biological context (1). The purpose of this paper is to propose that learning from the behavior of migrating animals in different environments may help to understand the behavior of migrating cancer cells within the different environments of the human body.

The ability of cancer cells to invade the stromal tissues, penetrate into vessels, and metastasize at sites distant from the original tumor are the features that define malignant tumors and determine the clinical outcome of the patient. Understanding the differential survival mechanisms of cancer cells in each step of the metastatic process is crucial for the development of target therapies and for the prediction of the patient’s prognosis.

Loss of cell-cell adhesion has been postulated as a key event for cancer cells to develop into tumors, migrate, and metastasize (2). However, the migratory patterns of cancer cells within vessels is still poorly understood. Cancer cells are often depicted as scattering within the intravascular fluid to reach their target destination (figure 1).  This letter postulates that this concept is not correct. The study of migration of organisms such as insects, may provide clues to understand cancer metastasis. The hypothesis is that there are similarities between the migration of cancer cells in different tissue environments and the migration patterns of insects such as termites and ants, in different physical landscapes. The migration of both cancer cells and insects is triggered by signals to form a new colony or by environmental stress. Similarly to cancer cells during stromal invasion, migratory insects scatter on land with limited and transient insect-to-insect contact. However, when approaching a liquid environment, both cancer cells (3) and insects form aggregates with more stable and increased contact (figure 2). This behavior is striking among fire ants, which can form closely packed aggregates with tread milling dynamics in liquids (4). The physics behind the aggregations formed by fire ants is currently being carefully studied by physicists (4,5). Their understanding of the interaction dynamics of fire ants in different environments will help in the development of materials with similar bond plasticity. Their findings indicate that in contrast to dense aggregates, small aggregates of fire ants in fluid are more unstable, decreasing their survival potential (5). This is also likely the case of migrating cancer cells within vessels. The changes of survival for individual cancer cells in the blood or lymph would be very limited, considering the organism immune macrophage response. The researchers also found that the ant aggregates elongate with increasing fluid flow (6), a mechanism which may be similar to aggregates of cancer cells in the flowing liquids of blood and lymph (figure 2).

In insects, such as ants and termites the goal of this distinct behavior is to maintain the integrity of the colony as a whole and to protect the eggs and queen from drowning (figure 2). The differential insect survival strategies will result in spreading and colonization (metastases) of different environmental landscapes.

The postulate of this paper is that cancer cells within vessels, similarly to fire ants, acquire cell-cell adhesion properties significantly different than those cancer cells scattering during invasion of stromal tissues. Aggregation of cancer cells within fluids would provide a safer format for the protection of those cells with reproductive potential, and ultimately for the survival and metastatic growth of the tumor. Thus, the differential survival mechanisms among migrating insects in different environments is equivalent to cancer metastases. Studying migrating insects can provide valuable clues to cancer researchers for the understating of cancer cell survival during tumor progression and metastasis. This could be particularly important for the study of mechanisms of cancer cell behavior within the liquid environment of lymphatics and blood vessels and for the development of adequate therapies.

Figure 1. Classical model to cancer invasion and metastasis. With permission from: Saxena M, Christofori G. (2013) Rebuilding cancer metastasis in the mouse. Mol. Oncol. 7(2):283-296.

Figure 2. Comparative images of fire ants in water safeguarding queen and eggs (with permission from Omar Villafranca, CBC News, Twitter, Aug. 27, 2017) and cancer cell aggregations within the liquid environment of a vessel (with permission from Dr. Dharam M. Rammani, Webpathology.com: A Collection of Surgical Pathology Images).

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References:

1. Peralta Soler A., Soler de Peralta, J. (2005) The Confabulatory Semiotics: Naming and Cognition of Diseases by Pathologists. Medicine, Health Care and Philosophy 8: 351-355.
2. Wijnhoven B.P.L., Dinjens W.N.M., Pignatelli M. (2000) E-cadherin-catenin cell-cell adhesion complex in human cancer. British J. of Surg. 87:992-1005.
3. Glinsky V.V., Glinsky G.V., Glinskii O.V., Huxley V.H., Turk J.R., Mossine V.V., Deutscher S.L., Pienta K.J., Quinn T.P. (2003) Intravascular Metastatic Cancer Cell Homotypic Aggregation at the Sites of Primary Attachment to the Endothelium. Cancer Res. 63: 3805-3811.
4. Wagner R.J., Vernerey F.J. (2022) Computational exploration of tread milling and protrusion growth observed in fire ant rafts. PloS Comput. Biol. (2022) 18(2): e1009869.
5. Ko H., Hagdu M., Komilian K., Hu D.L. (2022) Small fire ant rafts are unstable. Phys. Rev. Fluids 7. e090501, Sept. 2022.
6. Ko H., Yu T-Y., Hu D.L. (2022) Fire ant rafts elongate under fluid flows. IOPScience. Bioinspiration & Biomimetic. 17 (4): e045007.

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Biographical Details:

I obtained the medical degree in 1979 and PhD in 1986 from the National University of Cordoba, Argentina.

Since 1988 I worked in medical sciences research at the Unversity of Pennsylvania, Philadelphia, PA, and The Lankenau Institute of Medical Research, Wynnewood, PA.

After training in Pathology at the State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY and Cornell Medical College, New York, NY, I worked as a Pathologist at Duke University Medical Center, Durham, NC., and for about 10 years as a Dermatopathologist at the Richfield Lab., Cincinnati, OH.

I currently work as a Dermatopathologist at Inform Diagnostics Lab., in Needham, MA.

My interests include research topics in biology, medicine, evolutionary biology, art, particularly outsiders art, art history, prehistoric art, ceramics. I have been working in ceramics since childhood. Please see the page Civetceramics in Instagram for examples.

I am including a few selected publications to reflect some of those interests.

Peralta Soler A, Aoki A (1989) Estrogen influence on maturational pathway of mammary tumor virus: An immunoelectron microscopy study.  Exp. Mol. Pathol. 50: 16-25.

Peralta Soler A, Thompson KA, Smith RM, Jarett L (1989) Immunological demonstration of the accumulation of insulin, but not insulin receptors, in nuclei of insulin-treated cells. Proc. Natl. Acad. Sci. USA 86: 6640-6644.

Peralta Soler A, Knudsen KA (1991) Colocalization of N-CAM and N-Cadherin in avian skeletal myoblasts.  Develop. Biol. 148: 389-392.

Megosh L, Gilmour SK, Rosson D, Peralta Soler A, Blessing M, Sawicki JA, O’Brien TG (1995) Increased frequency of spontaneous skin tumors in transgenic mice which overexpress ornithine decarboxylase.  Cancer Res. 55: 4205-4209.

Peralta Soler A, Knudsen KA, Jaurand M-C, Johnson KR, Wheelock MJ, Klein-Szanto AJP, Salazar H (1995) The differential expression of N-cadherin and E-cadherin distinguishes pleural mesotheliomas from lung adenocarcinomas.  Hum. Pathol. 26: 1363-1369.

Peralta Soler A, Harner GD, Knudsen KA, McBrearty FX, Grujic E, Salazar H, Han AC, Keshgegian AA  (1997) The expression of P-cadherin identifies PSA-negative cells in epithelial tissues of male sexual accessory organs and in prostatic carcinomas: Implications for prostate cancer biology.  Am. J. Pathol. 151:471-478.

De Paul A, Bonaterra M, Peralta Soler A, Knudsen KA, Roth FD, Aoki A (2005) Soluble P- cadherin found in human semen. J Androl  26:44-47.

Peralta Soler A, Soler de Peralta J (2005) The confabulatory semiotics: Naming and cognition of diseases by pathologists. Med. Health Care and Phil. 8:351-355.

Peralta Soler A. (2020) Is the viral pandemic an evolutionary step towards asexual human reproduction? EdgeScience 43, Sept. (3)

Nature, Science