Gather Round: In vitro tumor spheroids as improved models of in vivo tumors

Continued efforts to understand cancer have progressed in parallel with tendencies of tumors to evade conventional treatments used to control tumor progression. Cancer cells fit the ‘survival of the fittest’ paradigm given the fact that they exist in an aberrant in vivo environment consisting of compromised blood supply, low oxygen concentration, large amounts of reducing equivalents, low pH and hypoxia to name a few [1]. This differs from the normal tissue environment, where a perfect homeostasis is maintained. These in vivo pathophysiological gradients play an important role in tumor progression and their response to treatment [2]. To illustrate this idea, we describe two of many examples where these gradients play an important role in determining the molecular basis of biological incongruities found in tumors. For instance, hypoxic conditions can make cells resistant to radio-ablative therapy because radiotherapy relies on DNA damage orchestrated by oxygen centered free radicals [3]. The gradient in glucose results in a gradient in cellular proliferation, resulting in a slower dividing cell population in the center of the tumor giving rise to cancer stem cells [4]. Thus, asking important questions about tumor progression and efficacy to drugs on cancer cells cultured as a conventional monolayer has little physiological relevance. Cancer cells cultured as 3D spheroids have brought cancer research a step closer to in vivo tumors by recreating the physiologically relevant gradients of factors such as nutrients, oxygen, pH and cellular proliferation (Figure 1). The past decade has seen several approaches for culturing cells as multicellular spheroids in which microfabrication and biomaterials have played important roles in facilitating new insights.