ancer is not a single disease confined to one tissue. It’s a dynamic, systemwide disorder that exploits the body’s own biological networks. This article explores how cancer testing has evolved from early animal models to today’s advanced in vitro and computational methods, and why understanding the whole organism remains essential for developing effective therapies.

Why Cancer Testing Requires Whole Systems

Cancer is a whole-body disease. As a result, efficacy and safety testing of cancer therapeutics has for many years called for the use of animals with fully integrated complex biological systems. This has made good sense, but it has also been increasingly criticized.

The “big picture” is that malignant tumors depend upon the “cooperation” of many normal cell types and physiological systems to survive and grow. The tumor must recruit cells from the bone marrow to form blood vessels and mesenchymal stem cells to form stroma; this is accomplished through the secretion of soluble chemoattractant cytokines. With a growing blood supply, tumors access oxygen and nutrients. Tumors must co-opt the host immune system to avoid cell death through normal immune system processes, and tumor cells must escape normal growth controls, proceed with uninhibited proliferation, and break down and invade surrounding normal tissue.

Cancer as Part of the Body’s Complex Biological Network

The human organism is an integrated network of organs and tissues with varying interactions and relies on diverse physiological systems with a complex network of systems and subsystems. The behavior of one system affects the dynamics of other systems with different relative contributions from individual organ systems that in turn interact dynamically and network collectively to produce health or disease. Structural and neuronal networks that control physiological systems lead to a high degree of complexity with varied coupling and feedback interactions.

The malignant tumor simply becomes another component of the organism, taking advantage of the normal organ and tissue interactions.

From Mice to Modern Models: A Brief History of Cancer Research

In the 1950s when George Hitchings and Gertrude Elion began the systematic search for anticancer drugs, there were no models of malignant disease. Their work involved studying nucleic acid metabolism in various organisms, including bacteria, protozoa, and viruses, and their anticancer breakthrough and Nobel Prize winning work came from exploiting differences in the metabolism of human cancer cells and normal cells. In 1954, Lloyd Law exposed mice to the carcinogen 3-methylcholanthrene and developed the L1210 leukemia cell line (a mouse-derived lymphocytic leukemia cell line) from the resulting ascites. L1210 leukemia grown intraperitoneally in mice or as a suspension cell culture was widely used for anticancer drug discovery in the 1960s and 1970s.

Howard Skipper brought mathematical modeling to cancer drug-hunting in the 1960s. Skipper realized that the growth of cancerous tumors followed the same principles of Gompertzian growth as do bacterial colonies. At the same time, Goldie and Coleman noted that for the drugs available at the time, the proportion as well as the absolute number of drug-resistant cells in a tumor increased over time. Many drug-dosing schemes and strategies were explored to achieve optimal therapeutic benefit, and this work was modeled in tumor-bearing mice. The belief was that cancer cure could be achieved with the proper dosing, scheduling, and duration of treatment. The limitation was that the sensitivity of critical normal tissues limited the doses of drug(s) which could be safely administered to patients.

During this time, models for cancer research were improving rapidly, and the development of immunodeficient mice allowed the growth of human tumors in an in vivo model. Very importantly, human genetics were also being elucidated. The details (the mutations which cause drug resistance) could be addressed, and new drug targets were defined and tested in human tumor xenografts in immunodeficient mice. It became clear that malignant tumor growth was supported by the complete human organism.

Balancing Animal Research and New Testing Approaches

Mesenchymal stem cells, mainly from bone marrow and adipose tissue, are recruited to the tumor microenvironment in response to cytokine signals produced by cancer cells and differentiate into cancer-associated fibroblasts which can induce epithelial-mesenchymal transition in tumor cells and allow colonization in distant tissues by circulating tumor cells. Immune cells, or leukocytes, also partner with the malignant tumor in the metastatic process.

The complex relationship between malignant tumor and the whole organism requires the use of complex biological systems for efficacy and safety testing of investigational therapeutics. As a result, using animals (mice, rats, dogs) with fully integrated complex biological systems became necessary. Safety testing in animals comes under criticism because researchers use healthy young animals (mice 6-8 weeks; rats 8 weeks; dogs 5-7 months), which are not representative of the oncology patient population. Older animals are not used, in part, due to the costs associated with holding the animals until they age and, in part, because of concerns that the compromised health of older animals may contribute to or exacerbate the adverse effects of investigational therapeutic agents.

However, in recent times the cancer research community has been challenged by FDA to decrease the use of animals in efficacy and safety/toxicity testing in favor of New Approach Methodologies (NAMs), such as induced pluripotent stem cells differentiated into specific cell types (cardiac cells, intestinal cells, lung cells, etc.), and in silico, in vitro, and ex vivo methods. In a way, these methods bring cancer research full circle back to cell culture models for testing potential new therapeutics. However, these in vitro models miss the critical nature of the integrated complexity of the whole organism. No doubt, these models will find a place in the armamentarium in the fight against cancer and will allow a decrease in the number of animals used in research but, for the reasons stated here, are unlikely to entirely replace the use of animals.

Looking Ahead: Integrating Complexity with Compassion

As scientific innovation pushes toward more ethical and human-relevant testing models, the challenge will be to preserve biological complexity without compromising compassion. The future of cancer research lies not in replacing one approach with another, but in integrating the best of each, combining new technologies that reduce animal use with models that still capture the full biological reality of disease. Only by embracing both innovation and biological truth can we continue to develop therapies that truly improve patients’ lives.