Central memory CD8 ؉ T cells (TCM) and effector memory CD8

This study demonstrates that in malignant melanoma, elevated levels of nuclear ß-catenin in both primary tumors and metastases correlate with reduced expression of a marker of proliferation and with improved survival, in contrast to colorectal cancer. The reduction in proliferation observed in vivo is recapitulated in B16 murine melanoma cells and in human melanoma cell lines cultured in vitro with either WNT3A or small-molecule activators of ß-catenin signaling. Consistent with these results, B16 melanoma cells expressing WNT3A also exhibit decreased tumor size and decreased metastasis when implanted into mice. Genome-wide transcriptional profiling reveals that WNT3A up-regulates genes implicated in melanocyte differentiation, several of which are down-regulated with melanoma progression. These findings suggest that WNT3A can mediate transcriptional changes in melanoma cells in a manner reminiscent of the known role of Wnt/ß-catenin signaling in normal melanocyte development, thereby altering melanoma cell fate to one that may be less proliferative and potentially less aggressive. Our results may explain the observed loss of nuclear ß-catenin with melanoma progression in human tumors, which could reflect a dysregulation of cellular differentiation through a loss of homeostatic Wnt/ß-catenin signaling.differentiation ͉ prognosis ͉ metastasis ͉ WNT5A ͉ B16 model ͉ microarray M alignant melanoma accounts for Ͻ5% of all skin cancers, yet is responsible for 80% of skin cancer deaths (1). The outlook for patients with metastatic melanoma remains quite bleak, with a 5-year survival rate of only 5%-15% that has not changed significantly over decades despite intensive efforts to develop an effective therapy. Although the molecular mechanisms underlying the formation and progression of melanoma remain unresolved, recent studies have implicated Wnt signal transduction pathways in melanoma biology (2), raising the question of whether this insight can be used to develop a therapy.

Expression of a single chemokine receptor gene, CCR7, increased B16 cell metastasis to draining lymph nodes, suggesting that cancer cells may co-opt normal mechanisms of lymph node homing during metastasis.

Chemokines and chemokine receptors are extensively and broadly involved in cancer metastasis. Previously, we demonstrated that epigenetic silencing of the chemokine CXCL12 sensitizes breast and colon cancer cells to endocrine signaling and metastasis to distant tissues. Yet, the precise mechanism whereby CXCL12 production by tumor cells regulates dissemination remains unclear. Here, we show that administration of CXCL12 extended survival of tumorbearing mice by potently limiting metastasis of colorectal carcinoma or murine melanoma. Because secreted CXCL12 is a mixture of monomeric and dimeric species in equilibrium, oligomeric variants that either promote (monomer) or halt (dimer) chemotaxis were used to dissect the mechanisms interrupting carcinoma metastasis. Monomeric CXCL12 mobilized intracellular calcium, inhibited cAMP signaling, recruited β-arrestin-2, and stimulated filamentous-actin accumulation and cell migration. Dimeric CXCL12 activated G-protein-dependent calcium flux, adenylyl cyclase inhibition, and the rapid activation of ERK1/2, but only weakly, if at all, recruited arrestin, stimulated actin polymerization, or promoted chemotaxis. NMR analyses illustrated that CXCL12 monomers made specific contacts with CXCR4 that were lost following dimerization. Our results establish the potential for inhibiting CXCR4-mediated metastasis by administration of CXCL12. Chemokine-mediated migration and β-arrestin responses did not dictate the antitumor effect of CXCL12. We conclude that cellular migration is tightly regulated by selective CXCR4 signaling evoked by unique interactions with distinct ligand quaternary structures.malignancy | functional selectivity | cellular idling | cancer therapeutics | chemokine oligomer C hemokines are chemoattractant cytokines that bind G-protein-coupled receptors and are mediators for many physiological processes including cell trafficking, angiogenesis, and embryogenesis (1-3). Chemokine receptor signaling is linked with cancer metastasis as well as infiltration of tumor-associated immune cells, neoangiogenesis, and proliferation (4, 5). Chemokines as primary mediators of metastasis were first identified by Muller and colleagues who implicated the chemokine receptor CXCR4 in tumor cell trafficking (6-8). At least 23 different cancers have been shown to express elevated levels of CXCR4, sensitizing these cancers to CXCL12 gradients in distant tissues (9). CXCL12 is constitutively expressed in the bone marrow, lungs, and liver, which are common tissues of metastatic growth. Efforts to block metastatic dissemination have mainly used small molecule antagonists of CXCR4 (10) to limit cancer malignancy (11, 12). However, this avenue has proven difficult to move into the clinic (5, 12), suggesting alternative strategies to interfere with CXCR4-guided metastatic homing (for example, by the use of agonists rather than antagonists) are required. Our previous data indicate that epigenetic silencing of the Cxcl12 promoter enhances metastasis of colonic and mammary carcinoma, implicating...

It is clear from large clinical studies that selected chemokine receptors are often up-regulated in a large number of common human cancers, including those of the breast, lung, prostate, colon, and melanoma. Chemokine receptors and their corresponding chemokine ligands have been demonstrated to play a number of nonredundant roles in cancer metastasis to vital organs as well as regional lymph nodes, the most frequent site of cancer metastasis. Chemokine receptors may potentially facilitate tumor dissemination at several key steps of metastasis, including adherence of tumor cells to endothelium, extravasation from blood vessels, metastatic colonization, angiogenesis, proliferation, and protection from the host response via activation of key survival pathways such as phosphatidylinositol-3 kinase and Akt. It is interesting that many of these roles are reminiscent of their functions in leukocyte and stem cell trafficking. Lastly, we discuss therapeutic applications for chemokine receptor antagonists in cancer therapy.

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Background Little is known about the relationship between intrinsic cardiac nerve activity (ICNA) and spontaneous arrhythmias in ambulatory animals. Methods and Results We implanted radiotransmitters to record extrinsic cardiac nerve activity (ECNA, including stellate ganglion nerve activity, SGNA; vagal nerve activity, VNA) and ICNA (including superior left ganglionated plexi nerve activity, SLGPNA; ligament of Marshall nerve activity, LOMNA) in 6 ambulatory dogs. Intermittent rapid left atrial pacing was performed to induce paroxysmal atrial fibrillation (PAF) or atrial tachycardia (PAT). The vast majority (94%) of LOMNA were preceded or co-activated with ECNA (SGNA or VNA), whereas 6% of episodes were activated alone without concomitant SGNA or VNA. PAF and PAT were invariably (100%) preceded (<5 s) by ICNA. Most of PAT events (89%) were preceded by ICNA and sympathovagal co-activation, whereas 11% were preceded by ICNA and SGNA-only activation. Most of PAF events were preceded only by ICNA (72%); the remaining 28% by ECNA and ICNA together. Complex fractionated atrial electrograms (CFAEs) were observed during ICNA discharges that preceded the onset of PAT and PAF. Immunostaining confirmed the presence of both adrenergic and cholinergic nerve at ICNA sites. Conclusions There is a significant temporal relationship between ECNA and ICNA. However, ICNA can also activate alone. All PAT and PAF episodes were invariably preceded by ICNA. These findings suggest that ICNA (either alone or in collaboration with ECNA) is an invariable trigger of paroxysmal atrial tachyarrhythmias. ICNA might contaminate local atrial electrograms, resulting in CFAE-like activity.

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