Tumor microenvironment signaling and therapeutics in cancer progression

Abstract Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell‐to‐cell and cell‐to‐ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non‐autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF‐β) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD‐1), Cytotoxic T‐Lymphocyte Associated Protein 4 (CTLA4), T‐cell immunoglobulin mucin‐3 (TIM‐3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C‐C chemokine receptor 4 (CCR4)‐ C‐C class chemokines 22 (CCL22)/ and 17 (CCL17), C‐C chemokine receptor type 2 (CCR2)‐ chemokine (C‐C motif) ligand 2 (CCL2), C‐C chemokine receptor type 5 (CCR5)‐ chemokine (C‐C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three‐dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti‐cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab‐on‐chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses

Long-Term Conservation Agriculture and Intensified Cropping Systems: Effects on Growth, Yield, Water, and Energy-use Efficiency of Maize in Northwestern India

Conservation agriculture (CA)-based best-bet crop management practices may increase crop and water productivity, while conserving and sustaining natural resources. We evaluated the performance of rainy season maize during 2014 under an ongoing long-term trial (established in 2008) with three tillage practices, i.e., permanent bed (PB), zero tillage (ZT), and conventional tillage (CT) as main plots, and four intensified maize-based cropping systems, i.e., maize-wheat-mungbean, maize-chickpea-Sesbania (MCS), maize-mustard-mungbean, and maize-maize-Sesbania) as subplot treatments. In the seventh rainy season of the experiment, maize growth parameters, yield attributes, yield, and water- and energy-use efficiency were highest at fixed plots under ZT. Maize growth parameters were significantly (P < 0.05) superior under ZT and PB compared with CT. Maize yield attributes, including cobs per m2 (7.8), cob length (0.183 m), grain rows per cob (13.8), and grains per row (35.6), were significantly higher under ZT than CT; however, no significant effect of cropping systems was found on maize growth and yield attributes. Zero tillage exhibited the highest maize productivity (4 589 kg ha−1). However, among the cropping systems, MCS exhibited the highest maize productivity (4 582 kg ha−1). In maize, water use was reduced by 80.2–120.9 mm ha−1 under ZT and PB compared with CT, which ultimately enhanced the economic water-use efficiency by 42.0% and 36.6%, respectively. The ZT and PB showed a 3.5%–31.8% increase in soil organic carbon (SOC) at different soil depths (0–0.45 m), and a 32.3%–39.9% increase in energy productivity compared with CT. Overall, our results showed that CA-based ZT and PB practices coupled with diversified maize-based cropping systems effectively enhanced maize yield and SOC, as well as water- and energy-use efficiency, in northwestern India