IntroductionNatural killer (NK) cells are cytotoxic and cytokine-producing lymphocytes, involved in the immune defense against viral infections and tumors. 1 Their homeostasis is regulated by cytokines and membrane associate receptors able to inhibit or activate cellular programs. 2 The inhibitory receptors are well characterized and described extensively in several reviews. [3][4][5] Triggering of NK cells depends largely on NK receptor member D of the lectinlike receptor family (NKG2D) and natural cytotoxicity receptors (NCRs): NKp46, NKp44, NKp30. 6,7 NCRs are involved in the recognition of several tumor cell lines, although their ligands remain elusive. 6 NKG2D recognizes the MHC (major histocompatibility complex) class I chain-related (MIC) protein A (MICA) and B (MICB); both are nonclassic class I molecules. The UL16-binding proteins (ULBP1-3 or RAET1 proteins; ULBP1-3 in this paper) are the second group of NKG2D ligands in humans. MICs are expressed during virus infection or cell transformation; ULBP expression in fresh tumor cells is essentially unknown; only long-term cultured in vitro cell lines have been looked at so far. [8][9][10] Cytotoxic T lymphocytes (CTLs) and interferons (IFNs) have a key role in tumor progression and tumor "immune-editing process." 11 MHC class I molecule loss is a frequent event in tumor progression and could prevent CTL recognition. However, theoretically, NK cells could recognize MHC class I-defective tumors, according with the "missing self hypothesis." 12 So far, only in mouse models NK cells were demonstrated to destroy in vivo lymphoma and melanoma tumors with reduced MHC class I expression and/or with high levels of activating target structures. [13][14][15] Even though almost 30 years ago human NK cells were discovered for their in vitro antitumor cytotoxicity, we still have little information concerning the regulation of their antitumor activity in vivo or ex vivo. 16,17 Therefore, several questions remain to be addressed to understand the antineoplastic potential of human NK lymphocytes:1. HLA class I molecules are reported to be down-regulated during solid tumor progression. 18 19,20 Other hematopoietic-derived cells can stimulate NK lymphocytes as described for dendritic cells (DCs). 21 The B-cell membrane-associated proteins CD40 and CD1 regulate natural killer cell cytotoxicity. [22][23][24][25] Furthermore, NK lymphocytes are specifically activated after bone marrow graft but not by other tissue transplantations. 26 They localize in lymph nodes and spleen, mainly in B-cell follicles and in the marginal zone. 27 Blood, spleen, and bone marrow are the anatomic districts where the highest number and activity of NK cells are present. 1 Taking together these considerations, hematologic malignancies (B-cell-derived tumors in particular) could be considered an appealing system to investigate the potential role of NK cells in the control of tumor progression.Multiple myeloma (MM) is a plasma cell-derived tumor. It is characterized by accumulation of plasma cells in th...
Neuronal excitation is regulated by energy metabolism, and drug-resistant epilepsy can be suppressed by special diets. Here, we report that seizures and epileptiform activity are reduced by inhibition of the metabolic pathway via lactate dehydrogenase (LDH), a component of the astrocyte-neuron lactate shuttle. Inhibition of the enzyme LDH hyperpolarized neurons, which was reversed by the downstream metabolite pyruvate. LDH inhibition also suppressed seizures in vivo in a mouse model of epilepsy. We further found that stiripentol, a clinically used antiepileptic drug, is an LDH inhibitor. By modifying its chemical structure, we identified a previously unknown LDH inhibitor, which potently suppressed seizures in vivo. We conclude that LDH inhibitors are a promising new group of antiepileptic drugs.
SummaryLow-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.
Vascular endothelial growth factor (VEGF)‐A is known to play an important role in tumor angiogenesis. Three additional members of the VEGF family, VEGF‐B, ‐C and ‐D, have recently been discovered. VEGF‐C and VEGF‐D are ligands for VEGF receptor‐3, which is expressed in the endothelium of lymphatic vessels. The expression of VEGF‐C is known to be associated with the development of lymphatic vessels. Therefore, it is conceivable that VEGF‐C and VEGF‐D might play a role in the development of lymphatic vessels in solid tumors. To obtain some clue as to this role, we developed a semi‐quantitative reverse transcription‐polymerase chain reaction method to investigate the mRNA expression levels of each VEGF family member in breast cancer. All the VEGF family members were expressed at different levels in seven human breast cancer cell lines explored. Although VEGF‐A and VEGF‐B expressions were detected in both node‐positive and node‐negative breast tumors, VEGF‐C expression was detected only in node‐positive tumors. VEGF‐D expression was detected only in an inflammatory breast cancer and a tumor which developed an inflammatory skin metastasis. These findings suggest a possible relationship between the expression level of VEGF‐C and/or VEGF‐D and the development of lymphatic tumor spread.
A new human breast cancer cell line, KPL-4, was recently isolated from the malignant pleural effusion of a breast cancer patient with an inflammatory skin metastasis. This cell line can be cultured under serum-free conditions and is tumorigenic in female athymic nude mice. Flow cytometric analysis revealed the expression of Erb B-1, -2 and -3. Dot blot hybridization showed a 15-fold amplification of the erbB-2. Reverse transcription-polymerase chain reaction analysis showed a detectable level of mRNA expression of all the Erb B family receptors. In addition, all the receptors were autophosphorylated under a serum-supplemented condition. Unexpectedly, transplanted KPL-4 tumours induced cachexia of recipient mice. A high concentration of interleukin-6 (IL-6) was detected in both the culture medium and the serum of mice. The weight of tumours significantly correlated with the serum IL-6 level. The antiproliferative effect of a humanized anti-Erb B-2 monoclonal antibody, rhuMAbHER2, was investigated. This antibody significantly inhibited the growth of KPL-4 cells in vitro but modestly in vivo. Loss of mouse body weight was partly reversed by rhuMAbHER2. These findings suggest that KPL-4 cells may be useful in the development of new strategies against breast cancer overexpressing the Erb B family receptors and against IL-6-induced cachexia. © 1999 Cancer Research Campaign
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