Cancer-stromal interactions: role in cell survival, metabolism and drug sensitivity

Abstract

It has been known for a long time that the interaction between cancer cells and tissue microenvironment plays a major role in cancer development, progression and metastasis. The biochemical aspect of cancer-stromal interactions, however, is less appreciated. This short review article first provides a brief summary of the communications between cancer cells and the tissue microenvironment by direct cell-cell interactions and by soluble factors, and then describes several biochemical pathways that are important for the interaction between stromal and cancer cells with respect to energy metabolism, redox balance, cell survival and drug resistance. The potential therapeutic implications of abolishing stromal protective mechanisms to overcome drug resistance are also discussed.

Figure 1

Molecular interaction between cancer cells and stromal cells leading to increased cancer cell survival and drug resistance. The dynamic interaction between cancer and stromal cells can be mediated through adhesion molecules and soluble factors, leading to activation of major signaling pathways involving JAK/STAT, Gli1/2, MAPK, PI3K/Akt, NFκB and increased expression of the downstream effectors including iNOS/NO, VEGF and anti-apoptotic proteins (Bcl-2, Bcl-xL, Mcl-1) in cancer cells. These survival pathways and anti-apoptotic molecules promote cell viability and drug resistance. Furthermore, stromal cells may also alter the tumor cell secretome including those required for tumor growth and dissemination, such as IL-18, CXCL1 and IL-8.

Figure 2

Biochemical crosstalk between cancer cells and stromal cells. Glucose uptake by cancer cells is highly active, due in part to high expression of GLUT1. in cancer cells, glucose is converted to pyruvate and then to lactate through glycolysis. The high concentration of lactate in cancer cells is exported out of the cells through the highly expressed MCT1 to avoid excessive cellular acidification. High expression of MCT1 on stromal cells enables the uptake of lactate, which can be used as a fuel to produce energy after its oxidation back to pyruvate for aerobic metabolism in the mitochondria of the stromal cells. The increased expression of LDH1 and PDH and reduced expression of LDH5 and PDK1 in stromal cells seem to facilitate this metabolism. The regenerated pyruvate in stromal cells can also be exported through MCT1 and reused subsequently by cancer cells to convert back to lactate, with a generation of NAD⁺ to support glycolysis. Stromal cells also produce asparagine to feed leukemia cells. Depletion of asparagine using asparaginase is an effective way to abrogate this feeding mechanism and thus can be used to treat certain leukemia such as ALL.