Comparison between tumors in plants and human beings: Mechanisms of tumor development and therapy with secondary plant metabolites.

Background: Human tumors are still a major threat to human health and plant tumors negatively affect agricultural yields. Both areas of research are developing largely independent of each other. Treatment of both plant and human tumors remains unsatisfactory and novel therapy options are urgently needed.

Hypothesis: The concept of this paper is to compare cellular and molecular mechanisms of tumor development in plants and human beings and to explore possibilities to develop novel treatment strategies based on bioactive secondary plant metabolites. The interdisciplinary discourse may unravel commonalities and differences in the biology of plant and human tumors as basis for rational drug development.

Results: Plant tumors and galls develop upon infection by bacteria (e.g. Agrobacterium tumefaciens and A. vitis, which harbor oncogenic T-DNA) and by insects (e.g. gall wasps, aphids). Plant tumors are benign, i.e. they usually do not ultimately kill their host, but they can lead to considerable economic damage due to reduced crop yields of cultivated plants. Human tumors develop by biological carcinogenesis (i.e. viruses and other infectious agents), chemical carcinogenesis (anthropogenic and non-anthropogenic environmental toxic xenobiotics) and physical carcinogenesis (radioactivity, UV-radiation). The majority of human tumors are malignant with lethal outcome. Although treatments for both plant and human tumors are available (antibiotics and apathogenic bacterial strains for plant tumors, cytostatic drugs for human tumors), treatment successes are non-satisfactory, because of drug resistance and the severe adverse side effects. In human beings, attacks by microbes are repelled by cellular immunity (i.e. innate and acquired immune systems). Plants instead display chemical defense mechanisms, whereby constitutively expressed phytoanticipin compounds compare to the innate human immune system, the acquired human immune system compares to phytoalexins, which are induced by appropriate biotic or abiotic stressors. Some chemical weapons of this armory of secondary metabolites are also active against plant galls. There is a mutual co-evolution between plant defense and animals/human beings, which was sometimes referred to as animal plant warfare. As a consequence, hepatic phase I-III metabolization and excretion developed in animals and human beings to detoxify harmful phytochemicals. On the other hand, plants invented "pro-drugs" during evolution, which are activated and toxified in animals by this hepatic biotransformation system. Recent efforts focus on phytochemicals that specifically target tumor-related mechanisms and proteins, e.g. angiogenic or metastatic inhibitors, stimulators of the immune system to improve anti-tumor immunity, specific cell death or cancer stem cell inhibitors, inhibitors of DNA damage and epigenomic deregulation, specific inhibitors of driver genes of carcinogenesis (e.g. oncogenes), inhibitors of multidrug resistance (i.e. ABC transporter efflux inhibitors), secondary metabolites against plant tumors.

Conclusion: The exploitation of bioactive secondary metabolites to treat plant or human tumors bears a tremendous therapeutic potential. Although there are fundamental differences between human and plant tumors, either isolated phytochemicals and their (semi)synthetic derivatives or chemically defined and standardized plant extracts may offer new therapy options to decrease human tumor incidence and mortality as well as to increase agricultural yields by fighting crown galls.