RANKL-induced CCL22/macrophage-derived chemokine produced from osteoclasts potentially promotes the bone metastasis of lung cancer expressing its receptor CCR4

Sadanandam

2007

Cancer Metastasis Rev

158

132

Chemokines are a large group of low molecular weight cytokines that are known to selectively attract and activate different cell types. Although the primary function of chemokines is well recognized as leukocyte attractants, recent evidences indicate that they also play a role in number of tumor-related processes, such as growth, angiogenesis and metastasis. Chemokines activate cells through cell surface seven trans-membranes, G-protein-coupled receptors (GPCR). The role played by chemokines and their receptors in tumor pathophysiology is complex as some chemokines favor tumor growth and metastasis, while others may enhance anti-tumor immunity. These diverse functions of chemokines establish them as key mediators between the tumor cells and their microenvironment and play critical role in tumor progression and metastasis. In this review, we present some of the recent advances in chemokine research with special emphasis on its role in tumor angiogenesis and metastasis.

Section: Chemokines and Their Receptors In Tumor Growth And Metastasismentioning

confidence: 60%

Section: Chemokines and Their Receptors In Tumor Growth And Metastasismentioning

confidence: 99%

Chemokines in tumor angiogenesis and metastasis

Sadanandam

2007

Cancer Metastasis Rev

158

132

“…SDF-1 gradients mediate HSC retention within BM niches, and growing evidence suggests that CXCR4-expressing cancer cells home to bone in a similar fashion, where they may lodge in the pre-existing supportive stromal microenvironment (Muller et al 2001;Kaifi et al 2005). Bone expresses particularly high levels of SDF-1, and osteotropic cancers such as breast, ovarian, prostate, and neuroblastoma metastasize to bones in a CXCR4-dependent manner (Ge- Furthermore, neutralization of the SDF-1/CXCR4 axis can block prostate metastasis and growth in osseous sites (Nakamura et al 2006). Differentiating osteoclasts constitutively produce chemokine CCL22 and may promote bone metastasis of lung cancer cells expressing its receptor CCR4 (Nakamura et al 2006).…”

Section: Changes In the Bm Microenvironmentmentioning

confidence: 99%

Migratory neighbors and distant invaders: tumor-associated niche cells

Wels

Kaplan²,

Rafii³

et al. 2008

Genes Dev.

356

302

The cancer environment is comprised of tumor cells as well as a wide network of stromal and vascular cells participating in the cellular and molecular events necessary for invasion and metastasis. Tumor secretory factors can activate the migration of host cells, both near to and far from the primary tumor site, as well as promote the exodus of cells to distant tissues. Thus, the migration of stromal cells and tumor cells among specialized microenvironments takes place throughout tumor and metastatic progression, providing evidence for the systemic nature of a malignancy. Investigations of the tumor-stromal and stromal-stromal cross-talk involved in cellular migration in cancer may lead to the design of novel therapeutic strategies.Understanding the complex biological networks at play in metastasis requires a precise detailing of the molecular and cellular pathways involved in local and systemic migration. The long prevailing model of invasion and metastasis has focused on the adhesive and migratory capabilities that are intrinsic to tumor cells (Hanahan and Weinberg 2000). Meanwhile, we are becoming increasingly aware that tumors are composed of genetically altered malignant cells along with a heterogeneous population of stromal cells, whose dynamic interactions can profoundly enhance tumor progression and metastasis. Through the production of chemokines, growth factors, and matrix-degrading enzymes (Table 1), supportive cells-including fibroblasts, immune cells, and bone marrow (BM)-derived stem and progenitor cells-support blood vessel formation, break down basement membrane barriers, and attract tumor cells to distant sites. Tumor cells are constantly giving instructions, not only by direct cell-cell interactions, but also by secreted factors that "activate" normal host cells at both proximal and distal sites to migrate, eventually developing permissive niches that, in return, promote tumor cell survival and proliferation. The focus of this review is on the cellular constituents of the primary and metastatic tumor microenvironments, with emphasis on their migratory pathways. We hope to convey that the tumor and host cell interaction is truly reciprocal; while host cells may support tumor cells, tumor cells in turn modulate the microenvironments within which they reside. Furthermore, we highlight that cancer is a systemic disease, encompassing collective cell movements of tumor and stromal cells that are a prerequisite for tumor cell invasion and metastasis. Intrinsic tumor cell migratory capabilitiesInherent to the metastatic process is the capability of tumor cells to migrate through connective tissue barriers comprising cell-cell adherent junctions, basement membranes, and interstitial tissue stroma. This intrinsic migratory behavior is highly dependent on the interplay between adhesive and proteolytic activities. Tumor cell down-regulation of proteins mediating cell-cell interactions, such as cadherins, leads to changes in cell signaling, actin-based cytoskeletal structure, and eventual dissociation from n...

Cancer Microenvironment

“…Chemokines and their corresponding receptors have established roles in directing cell migration in many different types of cancer; and expression levels of these proteins have also correlated with clinical outcomes [24][25][26][27][28][29]. The role of CCL25-CCR9 signaling in modulating metastasis was initially reported by Letsch There is an absence of CCL25 staining within the normal architecture of the pancreatic duct and stroma c. In the malignant pancreatic lesion, with characteristic nuclear crowding, enlarged nuclei, and rare mitoses, there is moderate heterogeneous immunostaining for CCL25 protein in the nuclei.…”

Section: Discussionmentioning

confidence: 99%

Paracrine Activation of Chemokine Receptor CCR9 Enhances The Invasiveness of Pancreatic Cancer Cells

Heinrich

Arrington

et al. 2013

Chemokine receptors mediate cancer progression and metastasis. We have previously examined chemokine receptor CCR9 expression in pancreatic cancer. Here, our objective was to evaluate pancreatic stellate cells (PSCs) as a source of CCL25, the CCR9 ligand, and as an activator of CCL25-CCR9 signaling in pancreatic cancer cells. CCL25 and CCR9 expression levels in human pancreatic cancer tissues and normal human pancreas were assessed by immunohistochemsitry. In vitro secretion of CCL25 in PSCs and PANC-1 cells was verified by enzyme-linked immunosorbent assay. Pancreatic cancer cell invasion was measured using a modified Boyden chamber assay with CCL25, PSC secreted proteins, and PANC-1 secreted proteins as the chemoattractant. There was immunostaining for CCR9 expression in human pancreatic tumor tissues, but not in normal pancreatic tissue. CCL25 expression was absent in the normal pancreatic tissue sample, but was observed in cancer cells and in the stromal cells surrounding the tumor. In vitro, both PANC-1 cells and PSCs secreted CCL25. In an invasion assay, exposure to CCL25, PSC-and PANC-1-conditioned media significantly increased the invasiveness of PANC-1 cells. Inclusion of a CCR9-neutralizing antibody in the invasion assay blocked the increase in invading cells elicited by the chemoattractants. Our studies show that pancreatic cancer invasiveness is enhanced by autocrine and paracrine stimulation of CCR9. PSCs in the tumor microenvironment appear to contribute to paracrine activation of CCR9. Investigations into CCR9 as a potential therapeutic target in pancreatic cancer must consider cancer cell autocrine signaling and also paracrine signaling from interactions in the tumor microenvironment.