Figure 2. RNA granules and tumor microenvironment.

Collective contributions from the different stress-associated conditions and surrounding cellular environment result in the unique niche where cancer cells exist, known as the tumor microenvironment (yellow). The tumor microenvironment changes dynamically during tumor progression, which requires constant adaptation of cancer cells to the changing intracellular and extracellular conditions. Hypoxia and nutrient starvation force cells to alter their metabolism/cellular energetics ultimately causing chronic ROS production that has multiple effects on cancer cell (patho)physiology. Chronic ER stress results from the imbalance between increased protein synthesis due to the high demands on cancer cell proliferation and ER capacity often. These stresses, often augmented by chemotherapy, trigger formation of PBs/SGs, spatial manifestations of ISR (Integrative Stress Response) that orchestrates cellular adaptation to changing conditions. The integration and balanced management of these cancer-associated stresses through SGs and PBS modulate multiple physiological responses (bottom red panel) including activation of anti-apoptotic, pro-survival mechanisms, enhanced tumor growth, modulation of immune responses, promotion of angiogenesis and/or activation of a novel developmental regulatory program/transformation referred to as the “epithelial-mesenchymal transition” (EMT). Multiple RNA-binding proteins with signaling properties (Ago2, RCK, TTP, YB-1, G3BP) and signaling molecules (RACK1, TRAF2, Raptor, mTOR) dynamically associate with SGs and PBs (double-headed arrows). They may transduce signals incoming from tumor microenvironment (yellow) to the physiological responses (bottom red panel), thus mediating both short- and long-term adaptations critical to tumor growth and metastasis. For other details, see text.