Nutritional stress alone can controlin vitrotumor formation and its invasive nature

Abstract

The metastatic nature is an inherent property of the tumor. However, the effect of the environmental stress conditions on tumor microcosm in the context of metastasis needs to be analyzed. This work is proposed to analyze the tumor behavior under multiple metabolic stress conditions, such as deprivation of glucose, protein, and oxygen. The spheroid proliferation rate is observed to be influenced profoundly by the stress level where minimal stress produces compact spheroid and severe stress make unstable aggregate like structures. It is observed that the non-invasive cancer cells cannot form spheroids under extreme stress.Stress conditions influence the mRNA levels of hypoxic, angiogenic and ECM deformation specific gene cluster. Spheroid reversal assay reveals the quiescent nature of the stressed spheroids under continuous stress conditions. However, after the rescue, the stressed spheroids were found to opt for different migration modalities. Extremely stressed noninvasive spheroids display atypical sprout-like growth within the invasion matrix and severely stressed spheroids can control the migration pattern of mesenchymal stem cells.Thus, it is concluded that multiple nutritional stress influence the spheroid formation and physiology along with the conversion of a non-invasive spheroids into quasi-invasive one. Introduction: Introduction:Cancer is one of the most fatal diseases due to its metastatic behavior. Tumors (>2-5 cm diameter) with a necrotic core, and a proliferating periphery initiate the shedding of metastatic cells and instigate the growth of occult tumors in other tissues 1 . Migration of tumor cells towards the greener pasture of future metastatic niches is a complex process.Therefore, understanding of metastasis at a molecular level has gathered much interest, because of its potential to provide much deeper insight into the tumor's social intelligence and probable cure 2 . Many factors such as tumor microenvironment, extra cellular matrix and the environmental stress are presumed to influence metastasis 3, 4 . Additionally inter-cellular conditions like deprivation of nutrition and oxygen are assumed to play influential role in angiogenesis and aggression of the tumor 5, 6 . Rapidly growing tumors utilize the available glucose inefficiently and initiate acidosis 7, 8 . Experimental deprivation of glucose is found to induce cell death in vitro while in xenograft studies it has been found to activate AMPK and ATF4 pathways to initiate angiogenesis 9, 10 . Similarly protein or amino acid (such as arginine) starvation induces apoptosis which can be bypassed through the GCN2/ATF4 Pathway 11, 12 . Hypoxic stress in cell culture condition induces apoptotic cell death and plays an important role in autophagy [13][14][15] . However in tumors hypoxic stress has also been highlighted as one of the most important factor to initiate angiogenesis and metastasis 16,17 . In fact, this multifaceted relationship between angiogenesis and metastasis seems to be synergistic in nature, as anti-angiogenic therapies ha...