The mechanisms responsible for recruiting monocytes from the bloodstream into solid tumors are now well characterized. However, recent evidence has shown that these cells then differentiate into macrophages and accumulate in large numbers in avascular and necrotic areas where they are exposed to hypoxia. This parallels their tendency to congregate in ischemic areas of other diseased tissues such as atherosclerotic plaques and arthritic joints. In tumors, macrophages appear to undergo marked phenotypic changes when exposed to hypoxia and to switch on their expression of a number of mitogenic and proangiogenic cytokines and enzymes. This then promotes tumor growth, angiogenesis, and metastasis. Here, we compare the various mechanisms responsible for monocyte recruitment into tumors with those regulating the accumulation of macrophages in hypoxic/necrotic areas. Because the latter are best characterized in human tumors, we focus mainly on these but also discuss their relevance to macrophage migration in ischemic areas of other diseased tissues. Finally, we discuss the relevance of these mechanisms to the development of novel cancer therapies, both in providing targets to reduce the proangiogenic contribution made by hypoxic macrophages in tumors and in developing the use of macrophages to deliver therapeutic gene constructs to hypoxic areas of diseased tissues. IntroductionMacrophages are essential cellular components of the innate immune system. They are released from the bone marrow as immature monocytes and circulate in the blood before extravasating into tissues, where they differentiate into resident macrophages. These cells can be found in almost all tissues of the body and, depending on the local microenvironment, acquire specialized phenotypic characteristics. Macrophages exhibit diverse functions, including phagocytosis, antigen presentation, antimicrobial cytotoxicity, and tissue remodeling as well as the secretion of a wide range of growth factors, cytokines, complement components, prostaglandins, and enzymes. 1 The presence of leukocytes in human tumors was first described by Virchow in 1863, who thought they reflected the onset of cancer at sites of previous chronic inflammation. It is now widely recognized that macrophages represent a prominent component of this leukocytic infiltrate in most malignant tumors and in some instances can comprise up to 50% of the cell tumor mass. 2,3 These cells, often called tumor-associated macrophages (TAMs), are thought to be almost entirely derived from peripheral blood monocytes recruited into the tumor from the local circulation (rather than resident macrophages present in the healthy tissue before the tumor developed). 4 The various possible roles of TAMs in tumor angiogenesis and progression have recently been reviewed extensively elsewhere. [5][6][7][8] Macrophages can exhibit direct cytotoxicity toward tumor cells in vitro by producing cytotoxic molecules such as tumor necrosis factor-alpha (TNF-␣), nitric oxide, and reactive oxygen intermediates as well as by...

Some chronic myeloid leukemia (CML) patients do not respond to imatinib, whereas others lose an initial response. To identify potential imatinib failures, we investigated the expression of imatinib uptake transporter (human organic cation transporter 1; hOCT1) and efflux transporters (ATP-binding cassette transporters ABCB1, ABCG2, and ABCC1) using real-time quantitative reverse transcription-polymerase chain reaction in 70 CML patients. Patients with high pretreatment hOCT1 expression had superior complete cytogenetic response (CCR) rates (P=0.008), progression-free and overall survival (P=0.01 and 0.004). Pretreatment ABCB1, ABCG2, and ABCC1 levels did not correlate with treatment outcome. Regression analysis demonstrated that pretreatment hOCT1 expression was the most powerful predictor of CCR achievement at 6 months (P=0.002). Imatinib uptake into a CML cell line with high hOCT1 expression was greater than into those with modest or low expression (P=0.002). The expression of hOCT1, but not efflux transporters, is important in determining the clinical response to imatinib.

Studies on the involvement of the human papillomavirus (HPV) in initiation and progression of oral neoplasia have generated conflicting results. The observed discrepancy is attributable mainly to the varying sensitivity of the applied methodologies and to epidemiologic factors of the examined patient groups. To evaluate the role of HPV in oral carcinogenesis, we analyzed 53 potentially neoplastic and neoplastic oral lesions consisting of 29 cases of hyperplasia, 5 cases of dysplasia, and 19 cases of squamous cell carcinomas, as well as 16 oral specimens derived from healthy individuals. A highly sensitive nested polymerase chain reaction (PCR) assay was used, along with type-specific PCR, restriction fragment length polymorphism analysis, dot blotting, and nonisotopic in situ hybridization. Nested PCR revealed the presence of HPV DNA in 48 of the 53 (91%) pathologic samples analyzed, whereas none (0%) of the normal specimens was found to be infected. Positivity for HPV was independent of histology and the smoking habits of the analyzed group of patients. At least one "high risk" type, such as HPV 16, 18, and 33, was detected by type-specific PCR in 47 (98%) infected specimens, whereas only 1 (2%) squamous cell carcinoma was solely infected by a "low risk" type (HPV 6). HPV 16 was the prevailing viral type, being present in 71% of infected cases. Single HPV 16 and HPV 18 infections were confirmed by restriction fragment length polymorphism. HPV 58 was detected by dot blotting in three hyperplastic lesions. HPV positivity and genotyping were further confirmed, and the physical status of this virus was evaluated by nonisotopic in situ hybridization. Diffuse and punctate signals, indicative of the episomal and integrative pattern of HPV infection, were observed for low-and high-risk types, respectively. Our findings are suggestive of an early involvement of high-risk HPV types in oral carcinogenesis.

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Prospective identification of patients whose chronic myeloid leukemia (CML) will progress to blast crisis is currently not possible. PP2A is a phosphatase and tumor suppressor that regulates cell proliferation, differentiation, and survival. Cancerous inhibitor of PP2A (CIP2A) is a recently described inhibitor of PP2A in breast and gastric cancer. The aim of this study was to investigate whether CIP2A played a role in CML and whether PP2A or its inhibitor proteins CIP2A or SET could predict clinical outcome. At the time of diagnosis of CML, patients who will later progress to blast crisis have significantly higher levels of CIP2A protein (P < .0001) than patients who do not progress, suggesting that PP2A is functionally inactive. We show that the potential mechanism for disease progression is via altered phosphorylation of the oncogene c-Myc. Knockdown of CIP2A results in increased PP2A activity, decreased c-Myc levels, and a decrease in BCR-ABL1 tyrosine kinase activity. We demonstrate that CIP2A levels at diagnosis can consistently predict patients who will progress to blast crisis. The data show that CIP2A is biologically and clinically important in CML and may be a novel therapeutic target. (Blood. 2011;117(24):6660-6668) IntroductionChronic myeloid leukemia (CML) is a malignant disease of the primitive hematologic cell, characterized by inappropriate expansion of myeloid cells. Although this disease is readily controlled by imatinib, approximately one-third of patients will eventually fail treatment 1,2 ; and a significant proportion of these will progress toward blast crisis (BC), which is usually rapidly fatal. Poor response to imatinib and progression to BC have been linked to high BCR-ABL1 tyrosine kinase activity, 3 but why one patient can remain in well-controlled chronic phase for decades whereas another may rapidly progress to BC is poorly understood.The BCR-ABL1 tyrosine kinase in CML is responsible for growth and survival of the malignant cells through activation of signaling pathways, such as the mitogen-activated protein kinase cascade and the PI3K pathway. 4,5 A major cellular serine/threonine phosphatase working to down-regulate activation of these pathways is the tumor suppressor protein phosphatase 2A (PP2A). 6 In CML cells, PP2A is a key target of BCR-ABL1 signaling; this protein becomes inactivated in these cells because BCR-ABL1 stimulates prevention of its auto-dephosphorylation at tyrosine 307 . 7,8 Maintenance of pY 307 -PP2A levels in CML cells feeds back to BCR-ABL1 and facilitates increased and sustained kinase activity. Inhibition of BCR-ABL1 by imatinib results in reactivation of PP2A, inducing both suppression of growth and enhanced apoptosis of the leukemic cells. 8 However, it is unknown whether Y 307 in PP2A is a direct substrate of BCR-ABL1, and the mechanism regulating phosphorylation of PP2A at this site is not clearly defined.One proposal for the mechanism through which BCR-ABL1 regulates PP2A activity in CML cells involves expression of the PP2A inhibitor protein SET. In ...