Bone Marrow Microenvironment and Tumor Progression

The bone marrow constitutes an unique microenvironment for cancer cells in three specific aspects. First, the bone marrow actively recruits circulating tumor cells where they find a sanctuary rich in growth factors and cytokines that promote their proliferation and survival. When in the bone marrow, tumor cells profoundly affect the homeostasis of the bone and the balance between osteogenesis and osteolysis. As a consequence, growth and survival factors normally sequestered into the bone matrix are released, further fueling cancer progression. Second, tumor cells actively recruit bone marrow-derived precursor cells into their own microenvironment. When in the tumors, these bone marrow-derived cells contribute to an inflammatory reaction and to the formation of the tumor vasculature. Third, bone marrow-derived cells can home in distant organs, where they form niches that attract circulating tumor cells. Our understanding of the contribution of the bone marrow microenvironment to cancer progression has therefore dramatically improved over the last few years. The importance of this new knowledge cannot be underestimated considering that the vast majority of cancer treatments such as cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy inflict a trauma to the bone marrow microenvironment. How such trauma affects the influence that the bone marrow microenvironment exerts on cancer is still poorly understood. In this article, the reciprocal relationship between the bone marrow microenvironment and tumor cells is reviewed, and its potential impact on cancer therapy is discussed

The capture of extracellular vesicles endogenously released by xenotransplanted tumours induces an inflammatory reaction in the premetastatic niche

The capture of tumour-derived extracellular vesicles (TEVs) by cells in the tumour microenvironment (TME) contributes to metastasis and notably to the formation of the pre-metastatic niche (PMN). However, due to the challenges associated with modelling release of small EVs in vivo, the kinetics of PMN formation in response to endogenously released TEVs have not been examined. Here, we have studied the endogenous release of TEVs in mice orthotopically implanted with metastatic human melanoma (MEL) and neuroblastoma (NB) cells releasing GFP-tagged EVs (GFTEVs) and their capture by host cells to demonstrate the active contribution of TEVs to metastasis. Human GFTEVs captured by mouse macrophages in vitro resulted in transfer of GFP vesicles and the human exosomal miR-1246. Mice orthotopically implanted with MEL or NB cells showed the presence of TEVs in the blood between 5 and 28 days after implantation. Moreover, kinetic analysis of TEV capture by resident cells relative to the arrival and outgrowth of TEV-producing tumour cells in metastatic organs demonstrated that the capture of TEVs by lung and liver cells precedes the homing of metastatic tumour cells, consistent with the critical roles of TEVs in PMN formation. Importantly, TEV capture at future sites of metastasis was associated with the transfer of miR-1246 to lung macrophages, liver macrophages, and stellate cells. This is the first demonstration that the capture of endogenously released TEVs is organotropic as demonstrated by the presence of TEV-capturing cells only in metastatic organs and their absence in non-metastatic organs. The capture of TEVs in the PMN induced dynamic changes in inflammatory gene expression which evolved to a pro-tumorigenic reaction as the niche progressed to the metastatic state. Thus, our work describes a novel approach to TEV tracking in vivo that provides additional insights into their role in the earliest stages of metastatic progression.The authors would like to thank Mrs. J. Rosenberg for her help in the formatting of the manuscript, and the personnel of the Core Facilities of the Saban Research Institute at Children's Hospital Los Angeles (Flow Cytometry, Extracellular Vesicle, Cell Imaging, and Animal Imaging Cores) for their expertise and assistance. This work was supported by National Institutes of Health/National Cancer Institute grant R01 CA207983 to Y.A. DeClerck

Crop pests and predators exhibit inconsistent responses to surrounding landscape composition

The idea that noncrop habitat enhances pest control and represents a win–win opportunity to conserve biodiversity and bolster yields has emerged as an agroecological paradigm. However, while noncrop habitat in landscapes surrounding farms sometimes benefits pest predators, natural enemy responses remain heterogeneous across studies and effects on pests are inconclusive. The observed heterogeneity in species responses to noncrop habitat may be biological in origin or could result from variation in how habitat and biocontrol are measured. Here, we use a pest-control database encompassing 132 studies and 6,759 sites worldwide to model natural enemy and pest abundances, predation rates, and crop damage as a function of landscape composition. Our results showed that although landscape composition explained significant variation within studies, pest and enemy abundances, predation rates, crop damage, and yields each exhibited different responses across studies, sometimes increasing and sometimes decreasing in landscapes with more noncrop habitat but overall showing no consistent trend. Thus, models that used landscape-composition variables to predict pest-control dynamics demonstrated little potential to explain variation across studies, though prediction did improve when comparing studies with similar crop and landscape features. Overall, our work shows that surrounding noncrop habitat does not consistently improve pest management, meaning habitat conservation may bolster production in some systems and depress yields in others. Future efforts to develop tools that inform farmers when habitat conservation truly represents a win–win would benefit from increased understanding of how landscape effects are modulated by local farm management and the biology of pests and their enemies

Les métalloprotéases matricielles et leurs inhibiteurs synthétiques dans la progression tumorale

Les métalloprotéases matricielles (MMP) constituent une famille de protéases impliquées dans la dégradation protéolytique de nombreuses protéines de la matrice extracellulaire mais aussi de protéines non matricielles. Ces protéases jouent un rôle important et complexe dans plusieurs étapes de la progression cancéreuse telles que la croissance tumorale, la prolifération des cellules cancéreuses et leur caractère invasif, la dissémination métastatique et l’angiogenèse. Les MMP sont donc devenues des cibles potentielles dans le traitement anti-cancéreux. Plusieurs inhibiteurs synthétiques ont ainsi été développés et ont montré une efficacité thérapeutique dans plusieurs modèles animaux de cancer. Les premiers essais cliniques réalisés avec ces inhibiteurs chez des patients cancéreux à un stade avancé ont cependant montré des effets mitigés

Le microenvironnement tumoral et la résistance thérapeutique

Au cours de la dernière décennie, il est devenu évident que le cancer n’est pas seulement une maladie causée par des gènes anormaux. Ainsi, le tissu avoisinant les cellules cancéreuses joue également un rôle important. De nombreuses interactions entre les cellules cancéreuses et le stroma tumoral, qui consiste en une matrice extracellulaire (MEC) et des cellules bénignes (appelées cellules stromales), favorisent la survie cellulaire et la résistance à la thérapie. Ces mécanismes sont maintenant connus et dépendent, soit d’un contact entre les cellules cancéreuses et la MEC ou les cellules stromales, soit de facteurs solubles ou de microvésicules. La moelle osseuse joue un rôle particulièrement important dans la résistance aux thérapies en tant que sanctuaire privilégié protégeant les cellules cancéreuses des effets toxiques de la chimiothérapie, mais aussi en tant que source de nombreuses cellules stromales qui colonisent la tumeur primaire et forment la niche prémétastatique. Cette meilleure connaissance des mécanismes par lesquels le microenvironnement tumoral favorise la résistance thérapeutique a conduit à des essais cliniques avec des agents qui ont pour fonction d’interférer avec les interactions entre cellules cancéreuses et stroma. Cette nouvelle voie de recherche clinique est particulièrement prometteuse

Inhibition of Collagenolytic Activity and Metastasis of Tumor Cells by a Recombinant Human Tissue Inhibitor of Metalloproteinases

Metalloproteinases secreted by tumor cells play an important role in metastasis. In the present study, we determined whether an inhibitor of these proteinases could inhibit the ability of tumor cells to degrade collagen and to metastasize. Metalloproteinases with degradative activities for type I collagen, type IV collagen, gelatin, and casein were secreted by a highly metastatic rat embryo cell line (4R) transfected by c-Ha-rasl (also known as HRAS1). These metalloproteinases were identified by sodium dodecyl sulfate substrate-poly-acrylamide gel electrophoresis as 92-kilodalton and 68-kilodalton gelatinolytic enzymes and 48-kilodalton and 45-kilodalton caseinolytic proteinases. A recombinant human tissue inhibitor of metalloproteinases (rTIMP) completely inhibited the proteolytic activities of these enzymes and was also a potent inhibitor of the proteolytic degradation of collagen by intact c-Ha-rasl-transfected cells. The ability of these cells to colonize the lungs after intravenous injection into nude mice was inhibited by 83% when rTIMP was repeatedly injected intraperitoneally into the animals. These data demonstrate that rTIMP is a potent inhibitor of the metalloproteinase activities of these cells and can also inhibit their metastatic potential. [J Natl Cancer Inst 82: 589–595, 1990

Cancer-Associated Fibroblasts: Understanding Their Heterogeneity

The tumor microenvironment (TME) plays a critical role in tumor progression. Among its multiple components are cancer-associated fibroblasts (CAFs) that are the main suppliers of extracellular matrix molecules and important contributors to inflammation. As a source of growth factors, cytokines, chemokines and other regulatory molecules, they participate in cancer progression, metastasis, angiogenesis, immune cell reprogramming and therapeutic resistance. Nevertheless, their role is not fully understood, and is sometimes controversial due to their heterogeneity. CAFs are heterogeneous in their origin, phenotype, function and presence within tumors. As a result, strategies to target CAFs in cancer therapy have been hampered by the difficulties in better defining the various populations of CAFs and by the lack of clear recognition of their specific function in cancer progression. This review discusses how a greater understanding of the heterogeneous nature of CAFs could lead to better approaches aimed at their use or at their targeting in the treatment of cancer

Contact with fibrillar collagen inhibits melanoma cell proliferation by up-regulating p27(KIP1)

It is known that the extracellular matrix regulates normal cell proliferation, and it is assumed that anchorage-independent malignant cells escape this regulatory function. Here we demonstrate that human M24met melanoma cells remain responsive to growth regulatory signals that result from contact with type I collagen and that the effect on proliferation depends on the physical structure of the collagen. On polymerized fibrillar collagen, M24met cells are growth arrested at the G(1)/S checkpoint and maintain high levels of p27(KIP1) mRNA and protein. In contrast, on nonfibrillar (denatured) collagen, the cells enter the cell cycle, and p27(KIP1) is down-regulated. These growth regulatory effects involve contact between type I collagen and the collagen-binding integrin α(2)β(1), which appears restricted in the presence of fibrillar collagen. Thus melanoma cells remain sensitive to negative growth regulatory signals originating from fibrillar collagen, and the proteolytic degradation of fibrils is a mechanism allowing tumor cells to escape these restrictive signals