Role of Tissue Microenvironment in Recruiting Macrophages During Apoptosis-induced Proliferation

Apoptosis-induced compensatory proliferation (AiP) is a mechanism that maintains tissue homeostasis after stress-induced cell death. During AiP, apoptotic cells induce proliferation of the neighboring surviving cells to compensate for tissue loss. AiP is important for wound healing and tissue regeneration in several model organisms. Additionally, AiP is an important feature of tumorigenesis and tumor relapse as it contributes to tumor repopulation following radiation or chemotherapy. Using an overgrowth tumor model (“undead tissue”) in Drosophila melanogaster, we determined that the initiator caspase Dronc promotes generation of extracellular Reactive Oxygen Species (ROS), which drive activation of the stress kinase JNK and downstream mitogens to promote AiP. We also observed increased numbers of Drosophila macrophages, termed hemocytes, which are attracted to undead tissue. However, the specific mechanisms by which macrophages are recruited to undead tissue are still unclear. Here, we report that the tissue microenvironment of the overgrown undead tissue directs macrophage recruitment during AiP. We demonstrate that ROS, JNK, and the matrix metalloproteinase Mmp2 are important for recruiting macrophages. Mechanistically, undead tissue-produced ROS and active JNK damage the basement membrane (BM) surrounding the undead tissue, by upregulating the expression and activity of Mmp2. The damaged BM then recruits macrophages to the undead tissue. Taken together, we propose a model in which the ROS-JNK-Mmp2 signaling axis damages the BM of undead tissue, resulting in changes in the tissue microenvironment that recruit macrophages to the area of damage to promote AiP and overgrowth

Basement membrane damage by ROS- and JNK-mediated Mmp2 activation drives macrophage recruitment to overgrown tissue

Macrophages are a major immune cell type infiltrating tumors and promoting tumor growth and metastasis. To elucidate the mechanism of macrophage recruitment, we utilize an overgrowth tumor model ( undead model) in larval Drosophila imaginal discs that are attached by numerous macrophages. Here we report that changes to the microenvironment of the overgrown tissue are important for recruiting macrophages. First, we describe a correlation between generation of reactive oxygen species (ROS) and damage of the basement membrane (BM) in all neoplastic, but not hyperplastic, models examined. ROS and the stress kinase JNK mediate the accumulation of matrix metalloproteinase 2 (Mmp2), damaging the BM, which recruits macrophages to the tissue. We propose a model where macrophage recruitment to and activation at overgrowing tissue is a multi-step process requiring ROS- and JNK-mediated Mmp2 upregulation and BM damage. These findings have implications for understanding the role of the tumor microenvironment for macrophage activation

The beneficial role of extracellular reactive oxygen species in apoptosis-induced compensatory proliferation

Apoptosis-induced proliferation (AiP) maintains tissue homeostasis following massive stress-induced cell death. During this phenomenon, dying cells induce proliferation of the surviving cells to compensate for the tissue loss, and thus restore organ size. Along with wound healing and tissue regeneration, AiP also contributes to tumor repopulation following radiation or chemotherapy. There are several models of AiP. Using an undead AiP model that causes hyperplastic overgrowth of Drosophila epithelial tissue, we recently demonstrated that extracellular reactive oxygen species (eROS) are produced by undead epithelial cells, and are necessary for inducing AiP and overgrowth. Furthermore, hemocytes, the Drosophila blood cells, are seen adjacent to the undead epithelial tissue, and may secrete the TNF ortholog Eiger that signals through the TNF receptor to active Jun-N-terminal kinase (JNK) in the undead tissue and induce proliferation. We propose that undead epithelial tissue triggers an inflammatory response that resembles recruitment of macrophages to human epithelial tumors, and that these tumor-associated macrophages release signals for proliferation and tumor growth of the epithelium. This Extra View article summarizes these recent findings with a focus on the role of eROS for promoting regeneration and inflammation-induced tumorigenesis

Advances in proton therapy in lung cancer

Lung cancer remains the leading cause of cancer deaths in the United States (US) and worldwide. Radiation therapy is a mainstay in the treatment of locally advanced non-small cell lung cancer (NSCLC) and serves as an excellent alternative for early stage patients who are medically inoperable or who decline surgery. Proton therapy has been shown to offer a significant dosimetric advantage in NSCLC patients over photon therapy, with a decrease in dose to vital organs at risk (OARs) including the heart, lungs and esophagus. This in turn, can lead to a decrease in acute and late toxicities in a population already predisposed to lung and cardiac injury. Here, we present a review on proton treatment techniques, studies, clinical outcomes and toxicities associated with treating both early stage and locally advanced NSCLC

Extracellular Reactive Oxygen Species Drive Apoptosis-Induced Proliferation via Drosophila Macrophages

Apoptosis-induced proliferation (AiP) is a compensatory mechanism to maintain tissue size and morphology following unexpected cell loss during normal development, and may also be a contributing factor to cancer and drug resistance. In apoptotic cells, caspase-initiated signaling cascades lead to the downstream production of mitogenic factors and the proliferation of neighboring surviving cells. In epithelial cells of Drosophila imaginal discs, the Caspase-9 ortholog Dronc drives AiP via activation of Jun N-terminal kinase (JNK); however, the specific mechanisms of JNK activation remain unknown. Here we show that caspase-induced activation of JNK during AiP depends on an inflammatory response. This is mediated by extracellular reactive oxygen species (ROSs) generated by the NADPH oxidase Duox in epithelial disc cells. Extracellular ROSs activate Drosophila macrophages (hemocytes), which in turn trigger JNK activity in epithelial cells by signaling through the tumor necrosis factor (TNF) ortholog Eiger. We propose that in an immortalized ( undead ) model of AiP, signaling back and forth between epithelial disc cells and hemocytes by extracellular ROSs and TNF/Eiger drives overgrowth of the disc epithelium. These data illustrate a bidirectional cell-cell communication pathway with implication for tissue repair, regeneration, and cancer

Variation in Management of Extremity Soft-Tissue Sarcoma in Younger vs Older Adults

A large proportion of extremity soft-tissue sarcomas (ESS) occur among young adults, yet this group is underrepresented in clinical trials, resulting in limited data on this population. Younger patients present many complex challenges that affect clinical management.To investigate variations in treatment management in young adults vs older adults with ESS.This multicenter retrospective cohort study used the National Cancer Data Base (NCDB) to identify patients 18 years and older with ESS who received definitive treatment (ie, limb-sparing surgery [LSS] or amputation) between 2004 and 2014. Data analysis was conducted in November 2019.Treatment regimen received among young adults (aged 18-39 years) and older adults (≥40 years) after diagnosis with ESS.To detect unique factors associated with treatment decisions in young adults with ESS, multivariable analyses used logistic regressions for patterns of treatment and their association with demographic factors and tumor characteristics.Overall, 8953 patients were identified, and among these, 1280 (14.3%) were young adults. From the full cohort, 4796 patients (53.6%) identified as male and 6615 (73.9%) identified as non-Hispanic White. More young adults than older adults underwent amputation (age 18-39 years, 104 of 1280 [8.1%]; age 40-64 years, 217 of 3937 [5.5%]; aged ≥65 years, 199 of 3736 [5.3%]), but the association was not statistically significant (age ≥65 years, odds ratio [OR], 1.49; 95% CI, 1.00-2.23; P = .05). Young adults were more likely to receive chemotherapy than older patients (age 40-65 years, OR, 0.52; 95% CI, 0.45-0.60; P = .001; ≥65 years, OR, 0.16; 95% CI, 0.12-0.20; P = .001). Conversely, young adults were less likely to receive radiation therapy compared with older patients (age 40-65 years, OR, 1.40; 95% CI, 1.22-1.61; P = .001; ≥65 years, OR, 1.33; 95% CI, 1.10-1.61; P = .003). Unique to younger adults, clinical stage II disease vs stage I and positive surgical margins were not associated with use of radiation therapy (stage II disease: OR, 1.25; 95% CI, 0.81-1.91; P = .31; positive surgical margins: OR, 1.43; 95% CI, 0.93-2.22; P = .11). White Hispanic young adults were less likely than non-Hispanic White young adults to receive radiation therapy (OR, 0.53; 95% CI, 0.36-0.78; P = .002).In this study, young adults with ESS were more likely to receive chemotherapy and less likely to receive radiation therapy than older adults. Further study is warranted to identify the clinical outcomes of these practice disparities