干细胞、肿瘤干细胞与肿瘤的关系

干细胞理论认为肿瘤是一种干细胞疾病，该理论为肿瘤的研究及治疗提供了新的方向和靶点。干细胞(stem cell)是一类具有自我更新和增殖分化能力的细胞，肿瘤细胞是一类具有无限增殖和失去分化为成熟细胞能力的细胞，肿瘤干细胞(cancer stem cell)是存在于肿瘤组织中的一小部分具有干细胞性质的细胞群体，能够驱使肿瘤的形成。本文拟综述干细胞、肿瘤干细胞与肿瘤发生发展之间的关系，为肿瘤的研究及临床治疗提供参考。     

癌症发生、转移的元凶——肿瘤干细胞

肿瘤干细胞是存在于肿瘤组织中的一小部分具有干细胞性质的细胞群体，它具有自我更新的能力，是形成不同分化程度肿瘤细胞和肿瘤不断扩大的源泉。人们对肿瘤干细胞的认识开始于研究肿瘤组织的克隆起源，通过镶嵌性联同工酶标记，已证买了肿瘤细胞的单克隆源性，进而逐渐形成肿瘤干细胞的概念。随着干细胞研究的不断深入，有关知识的     

BRAF突变在肿瘤克隆演化中的作用及研究进展

V-raf鼠肉瘤病毒癌基因同源体B(BRAF)编码丝裂原激活蛋白激酶信号通路上的丝氨酸-苏氨酸蛋白激酶，并参与着细胞的生长、增殖和分化。BRAF基因突变可以持续激活细胞外调节蛋白激酶，同肿瘤的发生发展相关。在内外环境的影响下，单克隆起源的肿瘤细胞中有增殖优势的细胞存活，而劣势细胞被淘汰，即肿瘤克隆演化。肿瘤的克隆演化常常与肿瘤细胞的异质性、恶性程度增高和耐药相关，其机制涉及肿瘤细胞、肿瘤微环境及局部免疫细胞的进化。针对BRAF突变型肿瘤克隆演化后的治疗仍无标准方案，目前探索性研究主要涉及相关通路的靶向抑制、异常蛋白和氨基酸的抑制及促进肿瘤细胞死亡。本文就BRAF突变型肿瘤的临床表型、演化机制及对肿瘤进化后的治疗性研究进行综述。     

肿瘤干细胞研究进展

肿瘤干细胞是存在于肿瘤组织中的一小部分具有干细胞性质的细胞群体，它具有自我更新的能力，是形成不同分化程度肿瘤细胞和肿瘤不断扩大的源泉。人们对肿瘤干细胞的认识开始于研究肿瘤组织的克隆起源，通过镶嵌性联同工酶标记，已证实了肿瘤细胞的单克隆源性^[1]，进而逐渐形成肿瘤干细胞     

肿瘤干细胞的起源

长期以来，肿瘤的发生和发展被认为是渐进的、多步骤、多环节的过程。例如基因突变的发生及其累积导致正常体细胞的信号转导及生长调控发生紊乱，促使细胞转化并进一步发展成为肿瘤细胞^[1]。肿瘤细胞曾被认为都具有无限增殖和再次形成肿瘤的能力。然而近年来，越来越多的研究结果表明肿瘤组织中绝大多数肿瘤细胞没有或仅具有有限的增殖能力，     

干细胞、肿瘤干细胞和SP细胞的关系及其研究进展

正常干细胞与肿瘤干细胞有许多相似之处，肿瘤干细胞可能起源于干细胞积累的突变。干细胞和肿瘤细胞均存在着SP细胞，SP细胞具有干细胞特性并高表达肿瘤多耐药蛋白ABCG2／BCRP1，SP细胞可能是肿瘤产生耐药和复发的原因。SP细胞为干细胞和肿瘤干细胞研究提供了有用的工具。     

RGD肽在肿瘤显像和治疗中的应用研究进展

介绍精氨酸（Arg）—甘氨酸（Gly）—天冬氨酸（Asp）肽（RGD肽）在肿瘤诊治领域应用研究新进展．内源性RGD肽存在于多种生物细胞外基质中，参与多条信号传导通路的活化，在多种生理和病理过程中发挥重要作用。外源性RGD肽与肿瘤细胞表面整合素结合后，可作为体内RGD肽类物质的竞争性抑制剂，从而能抑制肿瘤细胞与细胞外基质的黏附与迁移、抑制肿瘤血管形成、诱导肿瘤细胞凋亡。RGD肽能与肿瘤高表达的整合素受体结合，并从多个环节对肿瘤起到抑制作用，其具有靶向性进行肿瘤显像及肿瘤治疗的潜在应用价值。     

液基细胞学在肿瘤学研究中的应用

液基细胞学技术是现代细胞生物学和肿瘤细胞病理学研究的重大进展，具有较高的细胞收集率、筛查阳性率和病理符合率，现已广泛应用于各器官系统肿瘤的筛查和防治研究。现综述液基细胞学检查在肿瘤脱落细胞学和针吸细胞学方面的应用。     

H-2k^b和H-2D^b基因转染后对粘连素相关的肿瘤转移等非免疫学特征的不同影响

近年来的研究表明，MHC分子除具有参与免疫识别等免疫学作用外，还具有非免疫学的作用，这种作用主要与细胞粘附尤其是恶性肿瘤的转移有关，由于肿瘤细胞内在的非免疫学作用包括肿瘤细胞的生长、同型和异型细胞粘附、表面蛋白及糖基的表达等均与MHC Ⅰ类基因有关，使肿瘤的MHC Ⅰ类基因治疗成为如何降低肿瘤致瘤性和转移能力的热门解题。     

TRAIL及其在血液系统恶性肿瘤中的治疗进展

细胞凋亡（apoptosis）与肿瘤的发生、发展和转移有密切关系，诱导肿瘤细胞凋亡以达到治疗目的是近几年肿瘤治疗的热点之一。肿瘤坏死因子相关的凋亡诱导配体（TNF-related apoptosis-inducing ligand，TRAIL）是新近发现的TNF超家族成员，它能选择性的诱导肿瘤细胞和转化细胞发生凋亡，且与血液系统肿瘤常用的化疗药物具有协同性，还能克服一部分多药耐药现象，而对正常细胞没有显毒性效应，这些特性使TRAIL在血液系统恶性肿瘤的治疗中具有很大的应用前景。本就其结构、功能、作用机制及抗血液病肿瘤研究最新进展作一综述。     

Emerging technology: applications of Raman spectroscopy for prostate cancer

There is a need in prostate cancer diagnostics and research for a label-free imaging methodology that is nondestructive, rapid, objective, and uninfluenced by water. Raman spectroscopy provides a molecular signature, which can be scaled from micron-level regions of interest in cells to macroscopic areas of tissue. It can be used for applications ranging from in vivo or in vitro diagnostics to basic science laboratory testing. This work describes the fundamentals of Raman spectroscopy and complementary techniques including surface enhanced Raman scattering, resonance Raman spectroscopy, coherent anti-Stokes Raman spectroscopy, confocal Raman spectroscopy, stimulated Raman scattering, and spatially offset Raman spectroscopy. Clinical applications of Raman spectroscopy to prostate cancer will be discussed, including screening, biopsy, margin assessment, and monitoring of treatment efficacy. Laboratory applications including cell identification, culture monitoring, therapeutics development, and live imaging of cellular processes are discussed. Potential future avenues of research are described, with emphasis on multiplexing Raman spectroscopy with other modalities.     

Near-infrared Raman spectroscopy for optical diagnosis of lung cancer

Raman spectroscopy is a vibrational spectroscopic technique that can be used to optically probe the molecular changes associated with diseased tissues. The objective of our study was to explore near-infrared (NIR) Raman spectroscopy for distinguishing tumor from normal bronchial tissue. Bronchial tissue specimens (12 normal, 10 squamous cell carcinoma (SCC) and 6 adenocarcinoma) were obtained from 10 patients with known or suspected malignancies of the lung. A rapid-acquisition dispersive-type NIR Raman spectroscopy system was used for tissue Raman studies at 785 nm excitation. High-quality Raman spectra in the 700-1,800 cm(-1) range from human bronchial tissues in vitro could be obtained within 5 sec. Raman spectra differed significantly between normal and malignant tumor tissue, with tumors showing higher percentage signals for nucleic acid, tryptophan and phenylalanine and lower percentage signals for phospholipids, proline and valine, compared to normal tissue. Raman spectral shape differences between normal and tumor tissue were also observed particularly in the spectral ranges of 1,000-1,100, 1,200-1,400 and 1,500-1,700 cm(-1), which contain signals related to protein and lipid conformations and nucleic acid's CH stretching modes. The ratio of Raman intensities at 1,445 to 1,655 cm(-1) provided good differentiation between normal and malignant bronchial tissue (p < 0.0001). The results of this exploratory study indicate that NIR Raman spectroscopy provides significant potential for the noninvasive diagnosis of lung cancers in vivo based on the optic evaluation of biomolecules.     

Optical detection and grading of lung neoplasia by Raman microspectroscopy

The aim of this study was to investigate whether Raman spectroscopy could be used to identify and potentially grade lung neoplasia in cell samples. Normal human bronchial epithelial cells (HBEpCs) were analyzed by Raman spectroscopy and compared with (i) HBEpCs expressing human papillomavirus (HPV) type 16 E7 or CDK4; (ii) the immortalized bronchial epithelial cell line BEP2D and (iii) its asbestos-transformed derivative AsbTB2A. Overall, Raman spectroscopy, in combination with a linear discriminant analysis algorithm, was able to identify abnormal cells with a sensitivity of 91% and a specificity of 75%. Subdivision of the cell types into 3 groups, representing normal cells (HBEpCs), cells with extended lifespan (HBEpCs expressing HPV 16 E7 or CDK4) and immortalized/transformed cells (BEP2D and AsbTB2A) showed that Raman spectroscopy identifies cells in these categories correctly with sensitivities of 75, 79 and 87%, and specificities of 91, 85 and 96%, respectively. In conclusion, Raman spectroscopy can, with high sensitivity, detect the presence of neoplastic development in lung cells and identify the stage of this development accurately, suggesting that this minimally invasive optical technology has potential for lung cancer diagnosis.     

Effect of formalin fixation on the near-infrared Raman spectroscopy of normal and cancerous human bronchial tissues

Raman spectroscopy is a vibrational spectroscopic technique that can be used to probe molecular changes associated with tissue malignancy. In this report, the effect of formalin fixation on human bronchial tissues was studied by near-infrared (NIR) Raman spectroscopy to determine if the variations of Raman spectra caused by formalin fixation would affect the potential diagnostic ability for lung cancer detection. A rapid dispersive-type NIR Raman system with an excitation wavelength of 785 nm was used for this study. Bronchial tissue samples were obtained from six patients with known or suspected malignancies of the lung. Raman spectra of fresh normal and tumor tissue were compared with spectra of formalin-fixed normal and tumor tissue. Changes of the ratios of Raman intensities at 1445 to 1655 cm(-1) and 1302 to 1265 cm(-1) versus formalin fixing times varying from 2 to 24 h were also examined. The major tissue Raman peaks at 1265, 1302, 1445, and 1655 cm(-1) were found in both fresh and fixed bronchial tissues. However, bronchial tissue preserved in formalin showed a progressive decrease in overall intensities of these Raman peaks. Raman contaminations due to formalin were also found in the 980-1100, and 1480-1650 cm(-1) ranges with notable formalin peaks (1041 and 1492 cm(-1)) appearing in the fixed normal and tumor tissues. The results showed that NIR Raman spectra of human bronchial tissues were significantly affected by formalin fixing and tissue hydration. Diagnostic markers at the 980-1100, and 1500-1650 cm(-1) regions derived from fixed tissues do not appear to be applicable for in vivo lung cancer detection. To yield valid Raman diagnostic information for in vivo applications, fresh tissue should be used. If only fixed tissue is available, thorough rinsing of specimens in phosphate-buffered saline (PBS) before spectral measurements may help reduce the formalin fixation artifacts on tissue Raman spectra.     

Raman molecular imaging of brain frozen tissue sections

Raman spectroscopy provides a molecular signature of the region being studied. It is ideal for neurosurgical applications because it is non-destructive, label-free, not impacted by water concentration, and can map an entire region of tissue. The objective of this paper is to demonstrate the meaningful spatial molecular information provided by Raman spectroscopy for identification of regions of normal brain, necrosis, diffusely infiltrating glioma and solid glioblastoma (GBM). Five frozen section tissues (1 normal, 1 necrotic, 1 GBM, and 2 infiltrating glioma) were mapped in their entirety using a 300-µm-square step size. Smaller regions of interest were also mapped using a 25-µm step size. The relative concentrations of relevant biomolecules were mapped across all tissues and compared with adjacent hematoxylin and eosin-stained sections, allowing identification of normal, GBM, and necrotic regions. Raman peaks and peak ratios mapped included 1003, 1313, 1431, 1585, and 1659 cm^?1. Tissue maps identified boundaries of grey and white matter, necrosis, GBM, and infiltrating tumor. Complementary information, including relative concentration of lipids, protein, nucleic acid, and hemoglobin, was presented in a manner which can be easily adapted for in vivo tissue mapping. Raman spectroscopy can successfully provide label-free imaging of tissue characteristics with high accuracy. It can be translated to a surgical or laboratory tool for rapid, non-destructive imaging of tumor margins.     

Characterization of normal and malignant human hepatocytes by Raman microspectroscopy

Raman microspectroscopy was used to characterize normal and malignant hepatocytes in both cultured cells and human liver tissues. Consistent spectral changes were observed, including intensity increases at 1040 and 1083 cm⁻¹ with malignancy. A loss of intensity at 1241 cm⁻¹ was also observed in cancer cells, but was obscured in tissues by the overlap of a 1253 cm⁻¹ band, thought to originate from heme proteins. Normal liver tissue also differed from both the malignant tumor and its accompanying cirrhotic tissue at 1182 cm⁻¹. These results demonstrate the potential usefulness of Raman spectroscopy in clinical diagnosis, and investigations into the source of the observed spectral changes will provide information on the underlying mechanisms of carcinogenesis.     

Neuro-oncological applications of optical spectroscopy

Advances in optics and molecular imaging have occurred rapidly in the past decade. One technique poised to take advantage of these developments is optical spectroscopy (OS). All optical spectroscopic techniques have in common tissue interrogation with light sources ranging from the ultraviolet (UV) to the infrared (IR) ranges of the spectrum, and collection of information on light reflected (reflectance spectroscopy) or light interactions with tissue and emergence at different wavelengths (fluorescence and Raman spectroscopy). OS can provide information regarding intrinsic tissue optical properties such as tissue structure, nuclear density, and the presence or absence of endogenous or exogenous fluorophores. Among other applications, this information has been used to distinguish tumor from normal brain tissues, to detect tumor margins in intrinsic, infiltrating gliomas, to identify radiation damage to tissues, and to assess tissue viability and predict the onset of apoptosis in vitro and in vivo. Potential applications of OS include detection of specific central nervous system (CNS) structures, such as brain nuclei, identification of cell types by the presence of specific neurotransmitters, and the detection of optically labeled cells or drugs during therapeutic interventions. All have potential utility in neuro-oncology, have been investigated in our laboratories, and will be the subject of this review.     

Discrimination of parotid neoplasms from the normal parotid gland by use of Raman spectroscopy and support vector machine

Preoperative diagnosis of neoplasms in the parotid gland is essential for successful surgical treatment. The purpose of this study is to apply Raman spectroscopy in order to distinguish the spectral differences between pleomorphic adenoma and Warthin tumor from that of normal parotid gland tissues. Furthermore we establish the diagnostic model of the Raman spectra of neoplasms in parotid gland by employing support vector machine (SVM) with Gaussian radial basis function. Firstly, Raman spectra from different histopathological tissues were obtained by near-infrared Raman microscope, SVM was then employed to analyze the different spectra and establish a discriminating model. As a result, the differences of peaks in the region 800-1800 cm(-1) demonstrated the biochemical molecular alterations between different histopathological tissues. Compared with normal parotid gland tissues, the content of proteins, lipids and DNA increased in pleomorphic adenoma. The content of DNA increased but proteins and lipids decreased in Warthin tumor. SVM displayed a powerful role in the classification of three different groups. The sensitivities and specificities of discrimination between different groups reached above 95% and 99%, respectively. Raman spectroscopy combined SVM algorithm could have great potential for providing a noninvasive, effective and accurate diagnostic technology for neoplasm diagnosis in the parotid gland.     

Early detection of cervical neoplasia by Raman spectroscopy

Early detection of malignant tumours, or their precursor lesions, improves patient outcome. High risk human papillomavirus (HPV), particularly HPV16, infection can lead to the development of uterine cervical neoplasia, and therefore, the identification in clinical samples of the effects of HPV infection may have clinical value. In this report, we apply Raman microspectroscopy to live and fixed cultured cells to discriminate between defined cell types. Raman spectra were acquired from primary human keratinocytes (PHK), PHK expressing the E7 gene of HPV 16 (PHK E7) and CaSki cells, an HPV16-containing cervical carcinoma-derived cell line. Averaged Raman spectra showed variations, mostly in peaks originating from DNA and proteins, consistent with HPV gene expression and cellular changes associated with neoplasia, in both live and fixed cells. Principal component analysis produced good discrimination between the cell types, with sensitivities of up to 100% for the comparison of fixed PHK and CaSki. These results demonstrate the ability of Raman spectroscopy to discriminate between cell types representing different stages of cervical neoplasia. More specifically, this technique was able to identify cells expressing the HPV 16 E7 gene accurately and objectively, suggesting that this approach may be of value in diagnosis. Moreover, the ability to detect the effects of the virus in fixed samples also demonstrates the compatibility of Raman spectroscopy with current cervical screening methods. (c) 2007 Wiley-Liss, Inc.     

Detection of circulating tumor cells in human peripheral blood using surface-enhanced Raman scattering nanoparticles

The detection and characterization of circulating tumor cells (CTC) holds great promise for personalizing medicine and optimizing systemic therapy. However, low specificity, low sensitivity, and the time consuming nature of current approaches have impeded clinical adoption. Here we report a new method using surface-enhanced Raman spectroscopy (SERS) to directly measure targeted CTCs in the presence of white blood cells. SERS nanoparticles with epidermal growth factor peptide as a targeting ligand have successfully identified CTCs in the peripheral blood of 19 patients with squamous cell carcinoma of the head and neck (SCCHN), with a range of 1 to 720 CTCs per milliliter of whole blood. Our technique may provide an important new clinical tool for management of patients with SCCHN and other cancers.