Perspectives on tissue interactions in development and disease

Abstract

From the morphogenetic movements of the three germ layers during development to the reactive stromal microenvironment in cancer, tissue interactions are vital to maintaining healthy organ morphologic architecture and function. The stromal compartment is thought to be complicit in tumor progression and, as such, represents an opportune target for disease therapies. However, recent developments in our understanding of the diversity of the stromal compartment and the lack of appropriate models to study its relevance in human disease have limited our further understanding of the role of tissue interactions in tumor progression. The failure any model to fully recapitulate the complexities of systemic biology continue to create a higher imperative for incorporating various perspectives into a broader understanding for the ultimate goal of designing interventional therapies. Understanding this potential, this review examines the biological models used to study stromal-epithelial interactions and includes an attempt to incorporate behavioral terminology to define and mathematically model ecological relationships in stromal-epithelial interactions. In addition, the current attempt to incorporate these diverse ecological perspectives into in silico mathematical models through cross-disciplinary coordination is reviewed, which will provide a fresh perspective on defining cell group behavior and tissue ecology in disease and hopefully lead to the generation of new hypotheses to be empirically validated.

Fig. (1). Cell Origins in Organogenesis

The interacting tissues that induce pattern formation during organ development are derived from the 3 original germ layers: endoderm, ectoderm, and mesoderm. The final functional architecture of each organ is determined at different chronological stages and represents a systemic coordination of informational input, an example of which is seen in the hormonal regulation of urogenital sinus differentiation into either prostate or vaginal development based on the presence or absence of androgens. In general, mesoderm condenses around epithelium to direct budding, pattern formation and differentiation during organogenesis. Reciprocal interactions from the epithelium to the mesenchyme contribute to mesenchymal differentiation. (modified in part from [92]).

Fig. (2). Control of Bone Homeostasis

The constant balance of bone degradation and deposition necessary for proper bone function is achieved through a steady regulation of osteoclasts and osteoblasts, respectively. Osteoclasts resorb bone, which is then replaced by osteoblasts. This allows the body to regulate bone volume in response to physical and biochemical stresses, (e.g., weight bearing exercise results in increased bone density). Changes in the balance between resorption and deposition can result in weaker bones as seen in osteoporosis.

Fig. (3). Reactive stroma in wounds and cancer

The chronological regulation of acute wound repair of skin damage parallels some of the chronic responses of reactive stroma in cancer. In wound repair, immune cells are temporarily recruited to digest foreign substances and damaged cells whereas their chronic presence in cancer microenvironments is thought to exacerbate the loss of tissue homeostasis through a constant supply of stimulating growth factors. In addition, myofibroblasts are responsible for the reconstruction of tissue architecture through matrix deposition and wound contracture in wound repair, but are thought to disrupt tissue homeostasis in cancer by creating imbalanced tissue rigidity and proliferation.

Fig. (4). Defining new ecological relationships in tumors

Homeostatic signals produced by healthy tissues are lost during the transition to neoplasia due to a breakdown of appropriate relationships through proper architecture. New relationships between endogenous and infiltrating cells in tumors create a new environment. Potential new relationships in prostate cancer microenvironments include the recruitment of new blood vessels by tumor cells, which could be considered mutualistic since both benefit equally from the exchange; the competition for resources among various tumor phenotypes, which results in the environmental selection of the fittest cell types; and, the predatory digestion of tumor cells and the parasitic consumption of tumor cell resources by infiltrating immune cells, which represent two more examples of emergent relationships during tumorigenesis.