CELLULAR & MOLECULAR BIOLOGY LETTERS
https://www.doczj.com/doc/339481305.html,.pl
Received: 27 March 2008 Volume 14 (2009) pp 248-272
Final form accepted: 09 December 2008 DOI:10.2478/s11658-008-0048-z
Published online: 18 December 2008 ? 2008 by the University of Wroc ?aw, Poland
* Author for correspondence; e-mail: robaktad@csk.umed.lodz.pl, tel.: +48 42 689 51 91,
fax: +48 42 689 51 92
Abbreviations used: AJCC – American Joint Committee on Cancer; AML – acute myeloid
leukemia; AP-1 – activator protein 1; APC – antigen-presenting cell; CLL – chronic
lymphocytic leukemia; DC – dendritic cell; FADD – Fas-associated death domain; Flt3 –
FMS-like tyrosine kinase 3, FL – Flt3 ligand; HSP – heat shock protein; IFN-γ – interferon
gamma; IL-1R – Interleukin 1 receptor; IRF – interferon regulatory factor; LBP – LPS-
binding protein; LPS – lipopolysaccharide; MCP-1 – monocyte chemotactic protein 1; NF-
κB – nuclear factor kappa B; ODN – oligodeoxynucleotide; PAMP – pathogen-associated
molecular pattern; SOCS1 – suppressor of cytokine signaling 1; TGF-β – transforming
growth factor beta; TIR – Toll/Interleukin 1 receptor; TIRAP – TIR domain-containing
adapter protein or Mal; TLR – Toll-like receptor; TNF α – tumor necrosis factor alpha;
TRAM – TRIF-related adapter molecule; Treg – regulatory T cells; TRIF – TIR domain-
containing adapter inducing IFN β
Review
TOLL-LIKE RECEPTORS AND THEIR ROLE IN CARCINOGENESIS
AND ANTI-TUMOR TREATMENT
ANNA WOLSKA, EWA LECH-MARA ?DA and TADEUSZ ROBAK*
Department of Hematology, Medical University of ?ód ?, Cio ?kowskiego 2,
93-513 ?ód ?, Poland
Abstract: Toll-like receptors (TLRs) have been described as major components
of the innate immune system, recognizing the conserved molecular structures
found in the large groups of pathogens called pathogen-associated molecular
patterns (PAMPs). TLR expression is ubiquitous, from epithelial to
immunocompetent cells. TLR ligation triggers several adapter proteins and
downstream kinases, leading to the induction of key pro-inflammatory mediators
but also anti-inflammatory and anti-tumor cytokines. The result of this activation
goes beyond innate immunity to shape the adaptive responses against pathogens
and tumor cells, and maintains host homeostasis via cell debris utilization. TLRs
have already become potent targets in infectious disease treatment and vaccine
therapy and in neoplastic disease treatment, due to their ability to enhance
antigen presentation. However, some studies show the dual effect of TLR
stimulation on malignant cells: they can be proapoptotic or promote survival
CELLULAR & MOLECULAR BIOLOGY LETTERS 249 under different conditions. It is therefore crucial to design further studies assessing the biology of these receptors in normal and transformed cells. The established role of TLRs in human disease therapy is based on TLR7 and TLR4 agonists, respectively for the novel treatment of some types of skin cancer and for the anti-hepatitis B virus vaccine. Some clinical trials involving TLR agonists as potent enhancers of the anti-tumor response in solid tumors have begun.
Key words: Toll-like receptors, Innate immunity, Treatment, Carcinogenesis, Tumor, Vaccine, Dendritic cells
INTRODUCTION
Innate immunity is based on receptors that are able to recognize and respond to pathogens within minutes of an invasion, providing efficient protection against infectious agents. Among them are the Toll-like receptors (TLRs). These are activated by conserved pathogen-associated molecular patterns (PAMPs), which are essential for pathogen survival (e.g. the components of the cell wall, nucleic acids), and therefore do not mutate among large groups of microbes [1]. They take their name from the Toll protein first found in the 1990s in the Drosophila fruit fly; that protein is implicated in the dorso-ventral polarization of the embryo [2] but is also responsible for the antifungal immunity of the adult fly [3]. It was observed that the intracellular domains of the Drosophila Toll and mammalian Interleukin-1 receptor (IL-1R) had similar structures [4]. The Toll-like protein was shown to induce pro-inflammatory gene expression after ligation with specific PAMPs [5]. There are 11 human TLRs described out of a total of 13 mammalian TLRs, but ligands for some have yet to be discovered [6]. STRUCTURE AND ACTIVATION
TLRs belong to the type I transmembrane receptor family. The intracellular Toll/Interleukin-1R domains (TIR) required for downstream signaling have a striking similarity to IL-1R. The three-dimensional structure of the extracellular domain is responsible for ligand discrimination, eliciting an adequate immune reaction to a broad range of agonists attributed to their respective TLRs. According to an X-ray analysis of the extracellular domain of TLR, there is a capacity for direct but not exact engagement of PAMPs with TLRs [7]. Dimerization between TLRs enables further tailoring of the agonist recognition: e.g. the TLR1/TLR2 heterodimer responds to triacyl peptides, whereas TLR2/TLR6 recognizes diacyl peptides [8, 9]. There are six major families of TLRs, based on their phylogenetic backgrounds [10]. Each family is attributed to a general class of PAMPs. TLR2 belongs to the TLR2 family, with TLR1, TLR6 and TLR10, and it responds to various bacterial (lipopeptides, peptidoglycan, lipoteichoic acid), fungal (zymosan) and viral (viral core proteins) PAMPs [11-13]. TLR2 also cooperates with lectin receptors, enabling
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recognition of the fungal cell wall component zymosan [14, 15]. Double-stranded RNA and some synthetic RNA derivatives (polyinosilic-polycytidylic acid) are ligands for TLR3 [16, 17]. The ultimate lipopolysaccharide receptor is TLR4 [18]. It functions in a complex composed of the soluble LPS-binding protein (LBP), the membrane CD14 molecule, and the MD-2 glycoprotein that binds to the extracellular domain of TLR4 [19]. TLR5 has been shown to recognize an evolutionarily conserved domain of flagellin (a monomeric constituent of bacterial flagella) [20]. It has also been found on the basolateral side of intestinal epithelial cells and in the subepithelial compartment, indicating
its relevant role in microbial recognition and homeostasis at the mucosal surface [21]. The sixth family contains TLR7, TLR8 and TLR9. TLR7 and TLR8 are both predicted to recognize a nucleic acid-like structure, guanosine- or uridine-
rich single-stranded RNA (ssRNA), from viruses such as the human immunodeficiency virus and influenza virus [22]. ssRNA is abundant in the host. However, it is not detected by TLR7/8 due to the subcellular expression of these TLRs in the endosomes. Human TLR7 and TLR8 also recognize synthetic compounds: imidazoquinolines, which are currently approved in the treatment of genital warts, and loxoribine [23, 24]. TLR9 is a receptor for unmethylated CpG DNA motifs characteristic to bacterial DNA [25]. The function of this receptor has also been studied using synthetically designed oligodeoxynucleotides (ODNs) [26].
Some of the host molecules have also been found to contribute to TLR activation. They play an essential role in tissue repair, being released from necrotic but not apoptotic cells [27]. The so-called endogenous TLR agonists are capable of promoting the inflammatory response with maturation of dendritic cells into professional antigen-presenting cells (APC) [28, 29]. This allows for
the immune system to be involved in responding to danger signals such as tissue damage caused by trauma or infection. However, induction of the inflammatory reaction to heat shock protein 60 or 70 may contribute to the development of autoimmune diseases like type I diabetes [30] and Crohn’s disease [31]. Some researchers question the existence of such endogenous ligands. The reason is that TLR ligands may be contaminated with LPS during the process of production or purification, especially when manufactured by genetically modified E. coli strains [32, 33]. So far, only mRNA seems to be the true endogenous ligand for TLR3 [34]. Nevertheless, it is plausible that such reactions to minute amounts of endotoxin, not detectable using commercial testing kits, are due to the increased sensitivity of the studied cells to TLR stimulation. Kowalski et al. observed an excessive (more than 100-fold) responsiveness of peripheral blood mononuclear cells from patients with recent onset rheumatoid arthritis to LPS stimulation, compared to healthy controls and subjects diagnosed with degenerative arthritis [35]. That might also be the case
in experiments studying the influence of endogenous ligand preparations contaminated with minute amounts of LPS.
CELLULAR & MOLECULAR BIOLOGY LETTERS 251 TLR SIGNALING
The downstream pathway of TLR signaling requires two major adapter proteins, MyD88 and TRIF (TIR domain-containing adapter inducing IFNβ), which are exploited by all of the TLRs, and others that are exclusively utilized by TLR2 and TLR4: TIRAP (TIR domain-containing adapter protein or Mal) and TRAM (TRIF-related adapter molecule). Interaction of the TIR domains on TLRs and adapter molecules initiates a kinase cascade that induces transcription factors like nuclear factor-κB (NF-κB), AP-1, IRF3 and IRF7. Stimulating some TLRs results in the activation of specific adapter proteins, whereas others activate multiple adapter molecules. This enables the tailoring of the immune responses to different ligands, e.g. rapid antiviral response after IRF-3 activation through TRIF following TLR3 stimulation, and two-phase NF-κB activation subsequent to TLR4 ligation [for a review, see 36].
THE RESULTS OF TLR ACTIVATION – TLRs IN CARCINOGENESIS TLRs are very potent activators of gene transcription and translation. Murine macrophages initiate about 1000 LPS-responsive genes following TLR4 stimulation [37]. The activity of the transcription factor NF-κB is enhanced by TLR stimulation as early as 15-30 minutes after TLR ligation, with subsequent cytokine production occurring 2 hours later [38, 39]. The most evident consequence of TLR stimulation is the induction of the inflammatory response. TLR ligation results in the production of pro- and anti-inflammatory cytokines (IL-1, IL-6, IL-8, IL-10, TNFα) [40-42], chemokines (IL-8, MCP-1) [43, 44], defensins [45], and antiviral type-I interferons [46, 47]. Other mechanisms attributed to TLR signaling are processes including apoptosis, tissue repair and angiogenesis.
It has long been observed that chronic infection and inflammation are important factors contributing to the development of malignant tumors. For example, gastric cancer is linked to chronic Helicobacter pylori inflammation, and there is an association between chronic inflammatory bowel diseases and colon cancer [48, 49]. The chronic inflammatory process promotes the proliferation of cells and may promote the development of cancer. What’s more, the results of several studies imply that using non-steroidal anti-inflammatory drugs may lower the risk of some types of malignancies developing [50, 51]. The role of TLRs in mammalian cell biology seems overwhelming, and reaches far beyond the simple antimicrobial immune response of the innate immunity. Therefore, it has become even more tempting to scrutinize the Toll-like pathway in human diseases, especially in malignancies. TLRs are believed to be involved in tumor development and growth, with several possible mechanisms, but they have also been found in reactions directed against tumor cells (Tab. 1).
The factor that links chronic inflammation and tumor development is NF-κB [52]. It was found activated in a number of human malignancies, including acute
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Tab. 1. TLRs and tumor development and growth.
Tumor-promoting
TLR
References Anti-tumor TLR Reference Pro-angioge n ic 2, 9 58 Anti-angiogenic 7, 9 [59-61]
Proliferation 3, 4 64-67 Apoptosis 3, 4, 7, 9 [68, 70-72, 74] Chemoresistance 4 81,
82 Chemosensitivity 2,
4, 7 [83-86]
Treg activation 4, 5 93, 94 Treg inhibition
Antigen presentation
4, 5, 7, 8, 9 [94, 95, 98-102]
Cytotoxicity
9
[103,
106-109]
and chronic myelogenous leukemia, prostate cancer, multiple myeloma, and hepatocellular carcinoma [53-56]. Therefore, the agents that lead to the activation of NF-κB may be directly implicated in the development and progression of tumors. Toll-like receptors are potent activators of the NF-κB pathway. Their role in carcinogenesis depends on the activation of NF-κB and related genes, resulting in the production of cytokines such as IL-1, IL-2, IL-6, IL-10 and TNF-α; the recruitment of cells of the immune system by chemokines; the maintenance of chronic inflammation; and suppression in the tumor microenvironment. This complex net of chemical and direct cell-to-cell interactions may contribute to tumor survival and progression through an anti-apoptotic effect, the direct inhibition of cell cytotoxicity or angiogenesis [57, 58]. There is still controversy regarding TLRs in angiogenesis, as to whether they promote or inhibit the formation of new vessels. Pro-inflammatory cytokines and growth factors produced after TLR ligation favor angiogenesis, but at the same time, the synthetic TLR7 ligand (imiquimod) is found to halt this process and is a potent and approved topical anti-tumor agent in dermatological malignancies [59-61].
TLR expression has also been studied using tumor cells. The cells of several tumors display increased and changed TLR expression, and mice deficient in such receptors may be protected or develop fewer inducible tumors in experimental models [62, 63]. Moreover, the induction of TLRs on tumor cells may directly promote proliferation, such as in human prostate cancer and in head and neck cancer. This reaction is time- and dose-dependent and is reflected by NF-κB induction and the subsequent upregulation of oncoprotein c-Myc [64, 65]. However, there are studies suggesting a protective role of TLR stimulation and possible therapeutic options exploiting TLR ligation. A study of Paone et al. showed increased apoptosis of prostate cancer cells stimulated with the TLR3 agonist. This reaction may be due to the established balance favoring apoptosis rather than the proliferation of cancer cells under TLR ligation [68]. This balance may depend on the concentration of certain cytokines and the time of stimulation [69]. Direct TLR3 stimulation of melanoma cells leads to increased apoptosis. Moreover, TLR3-mediated cell death involves the activation of caspases and engages both the extrinsic and intrinsic apoptotic pathways. The
CELLULAR & MOLECULAR BIOLOGY LETTERS 253 results suggest that TLR3 agonists may be very promising adjuvants for cancer vaccines thanks to their newly identified direct cytostatic and cytotoxic effects on tumor cells [73]. Apoptosis may be a potent mechanism of eliminating acute myeloid leukemia cells (AML). Monocytic AML cell lines were found to be sensitive to IFN-α with LPS-induced apoptosis, which is partially dependent on caspase-8 recruitment and associated with enhanced Fas/CD95 expression.
A few samples of primary blast lines obtained from patients with AML also responded to the additive effects of LPS and IFN-α, indicating that sensitivity to TLR4-mediated inducible apoptosis is found in a fraction of AML samples with no correlation with FA
B phenotypes [74]. It has been observed that cells stimulated with TLR ligands udergo programmed cell death after NF-κB activation by Fas-associated death domain protein (FADD) and subsequent caspase recruitment [75-78]. This phenomenon reflects the regulatory capacity of TLR signaling protecting the host from excessive proliferation of immunecompetent cells being activated during inflammatory reactions, and may be implicated in an anti-tumor response enhanced with TLR stimulation. However, some studies have had completely contrary outcomes. Fas-FasL interaction with murine and human macrophages has been shown to enhance activation via TLR4 signaling. This surprising outcome is associated with the progression of chronic collagen-induced inflammation in a murine model [79]. Even more astounding is the observation that intact FADD protein is essential for TLR3- and TLR4-induced proliferation of B lymphocytes [80]. This dual role of TLRs in apoptosis is still indistinct, and reflects the complex associations between different signaling pathways in cells expressing TLRs.
The Toll-like pathway favoring tumor growth may also be triggered by chemotherapeutic agents themselves. Chemotherapeutics such as doxorubicin or paclitaxel can activate NF-κB and promote cell survival rather than apoptosis, which may explain the increased tumor growth despite the treatment reflecting some kind of chemoresistance [81, 82]. It may then be appropriate to assess the unique TLR expression pattern in tumor cells and direct the treatment according to the actual sensitivity to TLR stimulation. This would be plausible to overcome the undesirable NF-kB activation in prone individuals. On the other hand, studies show enhanced chemosensitivity upon TLR stimulation; for example, TLR7 ligation results in sensitization of the B cells of chronic lymphocytic leukemia to chemotherapeutic agents in vitro, presumably by impaired signal transduction through a stress-activated protein kinase pathway [83, 85].
In spite of these controversies, the potential of TLR agonists to drive and enhance the adaptive immune response against certain antigens has been investigated in anti-tumour therapy. Effective anti-tumor therapy has some major aspects that must be addressed. As tumor cells are capable of modulating the immune system, favouring survival and inhibiting anti-tumor responses, it is important to induce effective immunogenicity of tumor cells by augmenting antigen presentation. The other concern is the immuneparesis and tolerance towards malignant cells that accompany weak immunogenicity and are reflected
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by anti-inflammatory cytokine environment and naturally occurring regulatory
T cells (Treg) that mediate antigen-specific local immune suppression. Not only
do cells infiltrating the tumor seem to be reluctant to evoke anti-tumor reactions,
but they also create an inflammatory microenvironment that contributes to cancer growth and supports the immune suppression to tumor cells [87]. Regulatory T cells occur naturally during any immune response and function as inhibitors of excessive immunological reactions, but also act as suppressors of autoreactive effector T cells [88, 89]. Animals depleted of regulatory T cells suffer from lethal infections when exposed to infectious agents [90, 91]. They exert their suppressive function with a delay to effector T cells, allowing for an effective immune response against non-self antigens, and limiting its extent [92]. DCs play an important role in stimulating Tregs, but Tregs have also been described as being able to directly respond to TLR ligands. In murine models, Tregs have been found to express mRNA for TLR4, 5, 7 and 8. Ligation of TLR4 with LPS results in the augmentation of their suppressive function on cytotoxic T lymphocytes without support from DCs. Stimulated Tregs are fully functional and suppress cytotoxic T cells in vivo in LPS-challenged alymphoid animals [93]. However, another study demonstrates the dual action of TLR stimulation on the anti-tumor effects of Tregs. Tregs stimulated with flagellin at
the time of experimental tumor implantation exert their suppressive function and allow for tumor growth and progression, whereas delayed TLR5 ligation enhances the anti-tumor response reflected by the inhibition of tumor growth and
a decrease in Treg number. Contemporaneous administration of the TLR5 agonist favors a Th2 polarized response, in contrast to the increased IFNγ and Il-4 production characteristic for a Th1 response. Moreover, the addition of CpG oligodeoxynucleotides with early flagellin treatment was associated with complete tumor suppression, which demonstrates an as-yet unknown synergy between the TLR agonists against the tumor [94]. Other TLR agonists are capable of reversing the suppressive function of Tregs. In the study of Peng
et al., restoration of tumor growth inhibition was observed after the adoptive transfer of Tregs treated with poly-G oligodeoxynucleotides and CD8+ immunized T cells 3 days after tumor cell inoculation [95]. There is a lot of interest in Treg and TLR roles in anti-tumor immune responses. However, the kinetics of these reactions remain unknown and further studies need to be conducted.
Another possible way to overcome tumor-related immuneparesis is to augment
the immunogenicity of tumor cells and make them visible to the host immune system. Dendritic cells possess the ability to drive and ‘guide’ the adaptive immune responses. Their role involves presenting antigens and providing additional stimulating signals to na?ve T cells, thus enhancing effector reactions against given antigens. They also express TLRs and thus respond to a vast array
of microbial derivatives linking the innate and adaptive immunities. TLR ligation results in maturation and gaining the potential to activate na?ve T cells. Distinct PAMPs can have opposite effects regarding Th balance. For example,
CELLULAR & MOLECULAR BIOLOGY LETTERS 255 dsRNA, the TLR3 ligand, induces a strong Th1 reaction by releasing type I IFNs [96], and LPS from P. gingivalis (TLR2 agonist) induces DCs to prime a Th2-type response, whereas LPS from E. coli (TLR4 agonist) promotes the development of DC with Th1-polarizing activities through IL-12 [96]. DCs are also capable of reversing the Treg cell-mediated suppression after being stimulated with LPS and CpG oligodeoxynucleotides in vitro. This effect is accompanied by near to normal proliferation of effector T cells, and is independent of costimulation, but requires IL-6 [98]. Malignant cells may also become antigen-presenting cells. One of the most thoroughly studied hematological malignancies is chronic lymphocytic leukemia (CLL). Leukemic B cells are not capable of effective antigen presentation to T lymphocytes, and so are weakly immunogenic. However, as with normal B lymphocytes, CLL B cells express mRNA for TLR7 and TLR9, and are responsive to stimulation with TLR7 and TLR9 agonists. TLR7 ligation induces proliferation, increased expression of costimulatory molecules and TNF-α and IL-10 production. Additional IL-2 stimulation leads to inhibition of proliferation and IL-10 production. CLL B cells become more immunogenic to cytotoxic T lymphocytes in a mixed in vitro culture [99, 100]. Synthetic agonists of TLR9 also enhance proliferation, proinflammatory cytokine production and the transformation of CLL B cells to APCs in vitro [101]. They also induce up-regulation of the high-affinity IL-2 receptor in malignant compared to normal B cells. The addition of IL-2 to CpG-ODN-stimulated cells augmented proliferation in both normal B cells and B-CLL cells, but no costimulatory effect on cytokine production or surface molecule expression could be observed in normal B lymphocytes. By contrast, TNF-α and IL-6 production was increased in CLL cells, and the expression of CD80 and CD86 was further augmented when IL-2 was used as a costimulus. Autologous and allogeneic immune recognition of CLL B cells stimulated with CpG-ODN and IL-2 was increased compared with CLL B cells stimulated with CpG-ODN alone [102]. Furthermore, synthetic TLR9 ligands (oligodeoxynucleotides, ODN) bear the potential to enhance the immunogenicity of B-CLL cells by up-regulation of CD25, a target for immunotoxin LMB-2. LMB-2 was found to be much less toxic to normal B and T lymphocytes compared with B-CLL cells, and immunostimulatory CpG-ODNs efficiently sensitized B-CLL cells to a recombinant immunotoxin via modulation of its target [103].
However, in vivo studies of neoplastic diseases on animal models are most important, as the microenvironment of the tumor consists of interacting cells rather than individual reactions. In a study of an animal model of melanoma, continuous TLR2, 3, 4, or 7 stimulation elicits cytotoxic T-cell generation, but no in vivo effect on anti-tumor responses reflected by uninterrupted tumor growth and no signs of autoimmunity (vitiligo) in treated animals can be observed. Additional modification of the TLR signaling pathway including SOCS1 inhibition in DCs induces effective anti-melanoma immunity with marked IL-12 secretion and visible tumor growth suppression [104]. Moreover, genetic immunization along with TLR ligation is not efficient enough in the
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treatment of melanoma in mice, suggesting the existence of active tumor
immunotolerance. Hence, the treatment may be sufficient to slow the
progression of the primary tumor and reduce the number of metastases [105].
Last but not least is the phenomenon of tolerance, which is still controversial,
and is undermined by some authors. It is an effect of prolonged TLR stimulation,
which is supposed to protect the host from the detrimental activation of the
innate immune reaction following a microbial challenge. Animals exposed to
sub-lethal doses of LPS resist subsequent lethal doses. This is achieved by
entering a refractory state which is either expressed by a decrease in surface
TLR4 and impaired signal transduction (inhibited phosphorylation of the kinase
pathway, suppression of LPS-induced chemokine expression), or mediated by
anti-inflammatory cytokines [110-113]. Tolerance may be undesirable for anti-
tumor therapy when it is directed to increase tumor immunogenicity and antigen
presentation, but it would be of benefit in the case of inhibiting the regulatory
functions of Tregs. Several studies have investigated the phenomenon in human
cells using in vitro and ex vivo models. The results are quite surprising, as cells
stimulated with TLR2, TLR4 and TLR9 agonists in a 24-hour culture show
a sustained activation state rather than tolerance. Macrophages exposed to low
doses of LPS rapidly secrete TNFα, but when exposed to higher doses of LPS,
they progressively produce more cytokines (represented here by IL-1 and IL-12
promoter activation) [115]. The decreased responsiveness reflected by low levels
of proinflammatory cytokines appears to be due to the induction of the anti-
inflammatory cytokine milieu (IL-10 and Transforming Growth Factor-β; TGF-β)
[110, 115].
The role of TLRs in mammalian cell biology seems overwhelming and reaches
far beyond the simple anti-microbial immune response of the innate immunity.
Therefore, it has become even more tempting to scrutinize the Toll-like pathway
in the treatment of human diseases, especially in malignancies.
TLRs AS ANTI-TUMOR VACCINES
The potential of TLR ligands to induce appropriate and effective immune
reactions against a given antigen has been exploited in the vaccine therapy of
human melanoma (Tab. 2).
Tab. 2. TLRs in anti-tumor vaccine studies for melanoma.
TLR Vaccine Reference 7 Cancer/testis antigen + imiquimod [120]
Poly Melanoma antigen + Ribomunyl [121]
9 Melanoma antigen + CpG7909 [118]
7 Melanoma antigen + Flt3 + imiquimod [119]
TLR agonists have been shown to induce DC maturation and antigen
presentation, which is one of the issues to be addressed in the effective anti-
CELLULAR & MOLECULAR BIOLOGY LETTERS 257 tumor treatment. The rationale for designing studies with human tumors comes from animal models. Numerous studies have already been conducted on the use of TLR agonists along with tumor-antigen vaccination. The results are quite promising, showing the potential of TLR ligands to enhance and improve the efficacy of tumor vaccines. Adding TLR3, TLR4, TLR7 or TLR9 ligands potently activates CD8+ cytotoxic T cells with increased IFN-γ production and the leukocyte-rich immunostimulatory cytokine milieu at the tumor microenvironment [116-118]. Moreover, the most important evidence for the success of the combined treatment is the improved survival of tumor-bearing animals. However, studies in human malignancies reveal the great potential of TLR ligands but still mostly in in vitro models, which do not reflect the whole net of relationships between immunecompetent cells [119].
A pilot single-arm study was performed on 9 patients with malignant melanoma at stages II and III according to the AJCC criteria. The treatment included topical administration of imiquimod cream followed by intradermal injection with cancer/testis antigen formulation NY-ESO-1. The treatment was well tolerated, with only minor side effects at the site of administration and grade I systemic effects. In 4 of 9 patients, seropositivity for the tested antigen was observed. No CD4+ or CD8+ responses were detected, either by ELLISPOT or Delayed Type Hypersensitivity. However, CD4+ reactions were observed in in vitro sensitized cell cultures in 7 of the 9 study objects. No correlation between the clinical response and in vitro results was determined [120].
A phase I/II trial was conducted to evaluate clinical and immunological responses after intralymphatic and intranodal injections of mature dendritic cells loaded with specific tumor antigens and stimulated with a TLR ligand along with IFN-γ in patients with a metastatic melanoma. Fourteen patients enrolled in the study received 1 intralymphatic and 4 intranodal injections of DCs pulsed with melanoma antigens and matured in vitro with Ribomunyl (TLR ligand) and IFN-γ. Neither a complete nor partial response was observed. However, in 2 subjects, the lesions remained stable for up to 10 months and the longest survival was 48+ months. The median survival was 10.5 months. The most common adverse events included local reactions at the site of injection, and only
1 grade 4 lymphopenia occurred [121].
A study of Speiser et al. exploited another synthetic TLR ligand, CpG 7909. Eight patients enrolled in the study received vaccinations that consisted of the TLR9 agonist, melanoma antigen and incomplete Freund’s adjuvant. All the subjects exhibited strong antigen-specific T-cell responses, as assessed by the ex vivo secretion of IFN-γ and expression of granzyme
B and perforin. Furthermore, the frequency of Melan-A-specific T cells was one order of magnitude higher than the frequency seen in the 8 control patients treated similarly but without CpG. Moreover, T-cell clones recognized and killed melanoma cells in an antigen-specific manner in vitro [122].
In a study of Shackleton et al., 27 patients with metastatic or high-risk resected melanoma received the Flt3 ligand (FL); eighteen of them were treated with
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vaccination with melanoma antigens and 8 of the vaccinated subjects received
imiquimod topically [123]. The treatment was generally safe and well tolerated,
although some patients developed clinically significant toxicities related to FL.
FL induced increases in immature CD11c+ and CD123+ peripheral blood (PB)
DCs. Cutaneous reactions to peptide vaccination and circulating peptide-specific
CD8+ T-cells were more frequent in the imiquimod-treated patients. FL
treatment resulted in increased levels of circulating DCs, and stimulation with
tumor antigens augmented with the TLR ligand enhanced the maturation of
antigen-specific DCs.
TLRs IN CLINICAL TRIALS AGAINST HUMAN MALIGNANCIES
The promising role of the TLR pathway in the treatment of human malignancies
was studied in several clinical trials (Tab. 3).
Tab. 3. TLRs in clinical trials.
Reference
Malignancy TLR
Advanced-stage non-small-cell lung cancer TLR9 [124]
IV stage melanoma TLR7 [125]
IIIb/c or IV stage melanoma TLR9 [126]
Incompletely resectable pancreatic carcinoma TLR2/6 [127]
Recurrent non-Hodgkin lymphoma TLR9 [128]
Recurrent glioblastoma TLR9
[129] Recurrent non-Hodgkin lymphoma TLR9 [130]
Recurrent non-Hodgkin lymphoma TLR9 [131]
CLL, skin deposits TLR7 [132]
A randomized phase II trial of combination therapy with taxane and platinum
plus an additional synthetic TLR9 agonist was performed with the aim of
increasing the efficacy of a first-line treatment for the III and IV stage non-
small-cell lung carcinoma. One hundred and eleven patients were included in the
study. The major side effects concerning subcutaneous administration of ODN
were flu-like symptoms and local reactions, although grade 3 and 4 cytopenias
were more common in the TLR arm. The objective response rates (complete and
partial response) were 38% in the TLR9 agonist group and 19% in the
conventional treatment arm. Blinded independent radiological reviews of CT or
MRI scans from 90 patients with available scans in the study database revealed
similar results with respect to the confirmed objective response rate (19% in the
ODN plus chemotherapy arm, and 11% in the chemotherapy-alone arm;
p = 0.323). Statistical analysis suggests a trend toward improved survival for
patients treated with ODN plus chemotherapy. The median survival for patients
in the ODN plus chemotherapy arm was 12.3 months compared with 6.8 months
for patients in the chemotherapy-alone group [124].
CELLULAR & MOLECULAR BIOLOGY LETTERS 259 A phase II, multicenter, open-label study in patients with chemotherapy-refractory metastatic melanoma studied the anti-tumor activity of a systemically administered TLR7 agonist, 852A. Twenty one patients were enrolled and 13 completed the whole 12-week treatment cycle, with two discontinuing for adverse events considered to be possibly related to the study drug. A systemic, intravenously administered TLR7 agonist was well tolerated and was capable of inducing activation of the anti-tumor immune response assessed by serum IFN-γconcentration. Four (19%) patients had disease stabilization for > 100 days [125].
A phase II, open-label, single-arm study was designed for the evaluation of the safety and efficacy of a subcutaneous injection of the TLR9 agonist in patients with unresectable stage IIIb/c or stage IV melanoma. Twenty patients were enrolled in the study, and they received a mean of 10.7 injections of the TLR9 ligand. Adverse events included mostly flu-like symptoms of 1/2 grade, but in 3 patients, a slight increase in the anti-dsDNA antibody titre was observed with no clinical evidence of autoimmune disease. Two patients experienced a clinical response: metastatic leasion regression. One of these responses was ongoing at more than 140 weeks after TLR9 agonist therapy, whereas the other patient developed new leasions with regression of previous target ones. Three patients experienced stabilization of the disease, although all presented with progression at week 24. The markers of immunological activation showed increased DC activation with elevated levels of type I IFN, and induction of NK cell cytotoxicity [126].
A phase I/II trial was designed to assess the safety and efficacy of the Toll-like receptor 2/6 agonist MALP-2 in combination with gemcitabine in patients with incompletely resectable pancreatic carcinoma. Ten patients were included in the study, receiving an intratumoral injection of MALP-2 during surgery plus subsequent chemotherapy. The TLR2/6 agonist was well tolerated and induced clear local effects reflected by the influx of lymphocytes and monocytes, and the enhancement of NK activity. The most important effect was a 17.1 +/- 4.2-month increase in the mean survival, with 2 patients alive after 31 months, which is rarely seen with pancreatic cancer [127].
A phase I trial of the TLR9 agonist in patients with previously treated non-Hodgkin lymphoma (NHL) evaluated safety across a range of doses, and assessed immunomodulatory and clinical effects. Twenty three patients received up to 3 weekly infusions of ODN. Serious adverse events included cytopenias of grade 3/4, probably due to progression of the disease. There were no clinical responses at day 42, as assessed by imaging techniques [128].
A phase I trial of CpG-28, a TLR9 agonist, administered intratumorally by an intracranial catheter in patients with recurrent glioblastoma was designed to evaluate safety and clinical efficacy of the studied immunomodulator. Twenty four patients, refractory to previous therapies (chemo- and radiotherapy) were observed for at least 4 months. The main side effects were limited to worsening of neurological conditions, fever and transient grade 3 lymphopenia.
A minor response was observed in 2 patients with a reduced mass effect and
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decreased surrounding oedema, and the overall median survival was 7.2 months from the time of enrollment. At the time of analysis, 20 patients had died [129].
A phase I trial to investigate the safety, tolerability, and preliminary anti-tumor activity of PF-3512676 in combination with rituximab was conducted on patients with relapsed or refractory CD20 positive B-cell lymphoma. Fifty patients were included in the study. The main side effects and adverse events were mild to moderate systemic flu-like symptoms and injection-site reactions. Four patients experienced grade 3/4 neutropenia. Objective responses occurred
in 24% of patients overall [130].
Friedberg et al. investigated the influence of systemic administration of ODNs concurrently with rituximab on the disease course in 20 patients with non-Hodgkin lymphoma not responding to conventional chemotherapy. The regimen included once weekly administration of ODN with rituximab for 4 consecutive weeks. Drug tolerance and clinical efficacy were assessed. The most common side effects observed during the study were allergic reactions and skin irritation
at the site of administration, a cough, airway infection and a headache. A dose-related increase was measured in the expression of several interferon-inducible genes after CpG administration in peripheral blood mononuclear cells. Partial remission was achieved in 6 patients, while in 13 patients, the disease remained stable with a median progression-free survival of 12 months (from 5 to 23.5 months) [131].
Spaner et al. observed the regression of lymphomatous skin deposits in a CLL patient treated with a topically administered synthetic TLR7/8 agonist, imiquimod, which is approved for use against genital warts and basal-cell skin carcinoma [132]. Further clinical trials studying the efficacy of TLR ligands in
the treatment of human malignancies are ongoing.
CONCLUSION
Toll-like receptors comprise a family of pattern recognition receptors. The effects of their activation reach beyond innate immune reactions. Activating dendritic cells and modulating specific immune reactions at the levels of T and B cells link mechanisms of innate and adaptive immunity to elicit an efficient response against the invading pathogen or maintenance of homeostasis. However, TLR involvement in the pathogenesis of neoplastic diseases has also been observed. Some issues concerning the exploitation of TLRs in the treatment of neoplastic diseases still need to be addressed. It is crucial to adequately assess the expression of TLRs on transformed cells and study the biology of TLR signaling, as there are still some discrepancies among researchers about the functionality of TLRs in malignant cells. The functionality
of TLRs in transformed cells goes far beyond simple NFκB activation, but should be studied in the context of the tumor environment with its suppressive nature and weak immunogenicity.
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and Peyron, J.F. Activation of nuclear factor kappaB through the IKK complex by the topoisomerase poisons SN38 and doxorubicin: a brake to
营养与肿瘤的关系 1. 致癌原因 a) 外界致癌原因 b) 化学致癌 1) 多环碳氢化合物 2) 芳香胺类 3) 亚硝酸类 4) 其他 2. 物理致癌因素 a) A.电离辐射 b) B.日光及紫外线 c) C.纤维 d) D.热辐射 e) E.长期慢性机械性与炎性刺激 3. 生物致癌 a) 1.病毒 b) 2.寄生虫 c) 3.霉素及其毒素 4. 人体内部致癌的原因 a) 1)精神因素 b) 2)营养不均衡 c) 3)免疫力低下
d) 4)内分泌因素 e) 5)遗传因素 5. 癌细胞的特征 a) 1.分裂异常,速度快 b) 2.阔撒能力强,易转移 c) 3.善于攻占细胞间质组织对空间 6. 癌转移的原因 a) 1.人体缺钙时癌细胞粘着力强 b) 2.癌细胞会使“阿米芭”运动 c) 3.癌细胞在血液中可形成“栓”“癌” 7. 癌症的流行病学 a) 癌症是引起死亡的主要原因之一,根据1998年我国卫生部统计资料显示,在城市中占死因第一位,病死率为135.59/10万,它构成了对人类健康的极大威胁,也成为我国近年来研究和防治工作的重点 8. 癌症发病的原因与生成 a) 不良生活方式和环境因素可导致80%的癌症发病,癌瘤是机体一种细胞的异常增生,是一个多因子,多步骤,涉及内外环境,包括饮食营养、遗传、免疫、生命状态、生理病理等及其复杂的生物过程。 9. 癌的致病因素 a) 感染病毒：乙型和丙型肝炎病毒可致肝癌，乳头状瘤病毒可致子宫颈癌等。 b) 辐射：光中紫外线可致皮肤癌，Ｘ线，Ｙ线等电离辐射可致血液，淋巴系统癌，乳腺癌，甲状腺癌等。 c) 化学致癌物：煤烟，煤焦油中有多环芳烃，香烟中含有许多致癌成分，少量癌可能由工业致癌物如苯或石棉引起。 d) 食物性致癌物：黄曲霉素，杂环胺（高温烹调的肉类中含有）Ｎ－亚硝基化合物（存在于某些变质食物和蛋白质食物中也可在体内合成）以及
肿瘤专科医院国家癌症区域医疗中心设置标准 （2019年版） 目录 一、基本要求 (2) 二、医疗服务能力 (3) 三、教学能力 (5) 四、科学研究能力 (7) 五、癌症临床试验能力 (8) 六、承担公共卫生任务情况 (9) 七、落实医改相关任务情况 (10) 八、医院绩效 (11) 附表1.疑难危重症病种清单 (12) 附表2.疑难危重症病种清单 (12) 附表3.核心技术清单 (22)
一、基本要求 国家癌症区域医疗中心应当为三级甲等肿瘤专科医院或具备相应肿瘤专科能力的三级甲等综合医院，所处地理位置应当交通便利，方便区域内癌症患者就医，开展的诊疗科目齐全，有与之配套的完善的医技科室，有满足医疗、教学和科研所需的医疗仪器设备、高水平人才梯队和信息化水平，有健全的医院管理制度。医院具备较强的医疗服务辐射力和影响力，能够承担区域内疑难危重症的诊断与治疗、医学人才培养及医学科学研究等工作，其医疗技术水平、临床服务能力、医疗质量和安全、教学和科研能力达到国内或区域内领先水平。医院切实落实医疗机构依法执业主体责任。具体应当满足以下条件：（一）应当为三级甲等肿瘤专科医院或具备相应肿瘤专科能力的三级甲等综合医院； （二）近三年年均收治癌症患者≥5万人次，其中疑难危重病例数≥60%，肿瘤三级、四级手术病例占比≥85%； （三）肿瘤放射治疗年总人次≥5千人次，直线加速器≥5台，
并有后装近距离治疗设备； （四）年均病理会诊量≥1.5万次； （五）重症监护室（ICU）床位数占医院床位总数≥1%； （六）须获得肿瘤科国家临床重点专科建设项目。 二、医疗服务能力 主要临床专科（肿瘤外科、肿瘤内科、妇科、放射治疗科、影像诊断科、病理科、麻醉科等）医疗服务能力达到区域内领先水平；相应肿瘤专科护理能力达到区域内领先水平；具备组织开展临床研究的能力，配合国家癌症中心和国家肿瘤临床医学研究中心将临床科研成果向临床应用转化。 （一）临床/医技科室设置。能提供内科、外科、麻醉科、妇科、放射治疗科、影像诊断科（包括X线、CT、MRI等）、超声科、检验科、病理科、内镜科、重症医学科、输血科、核医学科、PET-CT中心、药剂科、营养科、中医科、疼痛科等诊疗服务。 （二）疑难病种诊疗能力。
丙酮酸脱氢酶与肿瘤的防治 正常细胞的能量代谢特点是使用葡萄糖在线粒体内进行氧化磷酸化 ( OXPHOS)，这种代谢方式既经济，效率也高。肿瘤细胞能量代谢的特点表现 在活跃地摄取葡萄糖，进行有氧糖酵解。这种看上去很不经济的能量供给方式 对肿瘤细胞却是必需的，它既为肿瘤细胞的不断生长提供能量，也为它们提供 了生物合成的原料。肿瘤细胞这种能量代谢方式早在20 世纪 20 年代就被德国 科学家Otto Warburg观察到，基于这一发现，Warburg提出假设:肿瘤细胞有氧糖 酵解的产生反映了线粒体呼吸链的破坏，而且，糖代谢的异常可视为肿瘤发生 的始动因素。大多数体内肿瘤细胞及体外的转化细胞，在氧气充足的情况下， 依然呈现葡萄糖高摄取率，增强的糖酵解代谢及代谢产物乳酸增加的这一现象 则是普遍存在，并被称之为Warburg Effect[1]。而在正常细胞中，ATP的产生主 要是通过OXPHOS，丙酮酸脱氢酶是连接糖酵解和Krebs的纽带，作为细胞进入 三羧酸循环的关键限速酶，在调节糖酵解和糖氧化磷酸化中起重要作用。因此，丙酮酸脱氢酶的活性可能与肿瘤的发生和发展有关系。 1、丙酮酸脱氢酶的简介 丙酮酸脱氢酶（PDH），是由丙酮酸脱氢酶E1α亚单位（PDHA1）和E1β 亚单位（PDHB）基因编码的α和β亚基组成的结合硫胺素焦磷酸盐（TPP）的异 四聚体[2]。Koike等[3]首先克隆和测序了编码人类PDHE1α和E1β亚单位的cDNA 序列。PDHA1的基因组DNA全长15.92kB，含有11个外显子，位于X染色体短臂上（Xp22.1~22.2）。其中含有保守的硫辛酸焦磷酸盐结合区，位于外显子6的 编码195氨基酸残基和外显子7的编码255氨基酸残基之间。此外，在4号染色体 上有一段与PDHA1同源的无内含子的序列，主要在睾丸组织表达。PDHB基因 位于3p13~q23，全长1.5kB，含有10个外显子。 在线粒体中，丙酮酸脱氢酶并不是单独存在的，而是以丙酮酸脱氢酶复合 体的形式存在。丙酸酸脱氢酶复合体（pyruvate dehydrogenase complex，PDHc）是定位在线粒体中的多酶复合物， PDHc包含3个催化酶和2个调节酶，以及3个 辅因子和1个结合蛋白。催化酶分别是丙酮酸脱氢酶（E1）、二氢硫辛酰胺转 乙酰酶E2和二氢硫辛酸脱氢酶E3。E3不是PDHc特定的，但是被其他两个丙酮 酸脱氢酶复合物组份共享，从而E3活性不足通常有超越预期分离的丙酮酸脱氢 酶复合体缺乏的后果。丙酮酸脱氢酶复合体的所有蛋白均是核编码的。高等生 物中丙酮酸脱氢酶复合体的快速调节主要是由PDH激酶（PDK）和磷酸酶(PDP）介导E1α亚基可逆性磷酸化实现的，丙酮酸脱氢酶E1α亚基存在三个磷酸化位点。而细菌的PDHc活性主要是通过别构效应来调节，PDHc缺陷导致代谢障碍，组 织受损[4]。 2、丙酮酸脱氢酶复合体的功能 PDHc是一组限速酶，催化丙酮酸不可逆氧化脱羧转化成乙酰辅酶A，同时
中国医学科学院肿瘤医院安全运维项目需求 2017-9
目录 一、项目概述2 二、服务需求2 2.1安全运维服务2 2.1.1渗透测试2 2.1.2安全加固3 2.1.3安全巡检4 2.1.4应急响应4 2.1.5安全预警4 2.1.6安全培训5 2.2安全咨询与安全检测服务5 2.3备案与测评服务6 2. 3.1备案服务6 2.3.2网站整改6 2.3.2三级系统测评服务6 三、服务要求6 四、资质要求7
一、项目概述 随着信息技术在医院业务与管理上的深入应用，医院信息系统、网络的安全性直接关系到医院的正常工作，因此需要引入专业的信息安全服务团队，建立一套安全运维与应急体系，根据医疗行业、国家以及国外的先进的信息安全标准，为我院提供全面、合规、先进的信息安全服务，保障我院业务系统及门户网站安全平稳运行，支持新建系统安全体系的建立与测评，逐步实现动态、完整、高效的信息安全体系。 二、服务需求 2.1安全运维服务 2.1.1 渗透测试 要求次数：一年一次 服务对象：现有重要系统（HIS、门户网站、PACS、LIS、OA等） 对用户选定的渗透对象，按照国际通用的PETS渗透测试标准，进行深入的模拟黑客攻击的渗透测试。测试中为保证整个渗透测试过程都在可以控制和调整的范围之内，以人工渗透为主，并辅助用户认可的渗透测试工具，发现业务和应用系统中的安全隐患，要求测试者有较强的专业技能，可以准确发现逻辑性更强、更深层次的弱点。 通过渗透测试发现业务系统存在的可能被利用的安全隐患，提出解决方案，协助用户进行全面的安全加固。 具体的渗透测试手段包括但不限于： 1）已知漏洞攻击 通过被披露的操作系统及应用软件（或模块）的安全漏洞，利用这些漏洞及相关工具对网站及其应用进行测试。
2017中国肿瘤登记年报 国家癌症中心隶属于中国医学科学院肿瘤医院，是国家肿瘤临床医学研究、肿瘤防治研究和信息交流的中心，定期出版全国肿瘤登记年报和专业学术期刊。 2017年2月，国家癌症中心发布了中国最新癌症数据，汇总了全国347家癌症登记点的数据。中国癌症统计一般滞后3年，所以这次最新公布的是2013年的发病和死亡数据。 2017年的报告显示：每天约1万人确诊癌症，平均每分钟就有7人确诊。
本次癌症统计，根据总结分析，有以下4大显著风险： 我们来详细分析一下数据： 1、中国是癌症大国，癌症病人占全球癌症病人总量的将近40%
●与2012年相比，中国癌症新发人数继续上升，从358万增加到368万，增幅3% ●同年，世界新发病例约1409万。中国新发癌症病例占世界的1/4 2、中国癌症发病率有显著的年龄区隔：40岁是分水岭，之前较低，之后迅速拉升，80岁是高峰 ● 40岁之前，处于较低水平，之后以后开始快速升高，80岁达到峰值； ●城市女性在20-50岁之间，癌症发病率均高于同龄男性； ●中国城市居民0-85岁，累计癌症发生风险为36%
3、中国癌症发病率城市区别：发病率U型分布，中型城市发病率最低 ●中国大/中/小城市的癌症平均发病率差异明显，发病率呈"U"型； ●中等城市男女平均癌症发病率最低 4、中国癌症发病率人群分布：小城市男性+大城市女性风险最高
●随着城市化的发展，男性癌症风险逐渐降低，小城市男性风险最高； ●女性患癌风险与男性相反，大城市女性癌症风险最高 5、城市地区TOP10高发癌症 ●消化道癌症：中国人主要的癌症负担，占男性全部癌症的50%左右； ●肠癌：城市女性增长趋势明显，主要与不健康饮食、久坐、腰围增粗有关； ●甲状腺癌：城市女性需要特别关注。 6、TOP10男性高发癌症
北京协和医学院肿瘤医院在职研究生课程班 肿瘤学放射物理方向招生简章 为帮助临床在职人员在原有基础上进一步提高学术水平，掌握坚实的理论基础和系统的专业知识，进而为社会培养更高层次肿瘤学专业人才，肿瘤医院在北京举办肿瘤学放射物理专业研究生课程班。 一、招生条件： 1、拥护《中华人民共和国宪法》，遵守法律、法规，思想政治表现好；优秀业务骨干；身体健康，并能坚持在职学习者。 2、大学本科毕业，并获得学士学位后，工作两年以上。有一定科研成果者，可申请硕士学位。 3、大专学历者，可参加研究生课程班的学习，但不能申请硕士学位。 二、课程设置和授课形式： 1、课程设置：放射治疗机原理、临床剂量学、放疗计划设计、放疗质控方法、特殊照射技术、医学成像原理、放射生物学、放射肿瘤学、辐射防护。 2、授课形式：所有课程均采用面授方式，课程形式为脱产、集中授课。 三、学习年限及收费 1、学习年限：半年，2013年8月至2014年2月。 2、学费：2万元，在入学注册时一次交清。学员注册缴费后如中途退学不再退费。学费只含课程费和正常组织的考试费；交通、食宿、教材及资料费等由学员自理。 四、学员结业及证书 1、研究生课程班的学员，完成规定的课程，考试成绩合格者（60分以上）即可结业。 2、结业学员名单和成绩报经研究生院审查核准后，颁发由北京协和医学院研究生院盖章的《研究生课程班结业证书》。 五、申请硕士学位办法 1、获得《研究生课程班结业证书》，申请学位四年有效。
2、在我校申请专业学位人员须参加我院临床训练至少半年。 3、通过同等学力人员申请硕士学位外国语水平全国统一考试。 4、考试合格的学员由肿瘤医院安排导师指导完成硕士毕业论文。 5、在核心期刊上发表第一作者论著1篇。 6、其他按照北京协和医学院有关规定办理。 六、报名须知： 1、报名方式和截至日期：电话、网络、现场报名均可。网上填写并打印 我院所《进修申请表》，单位盖章后，并将本人身份证、本科毕业证、学位证、医师资格证和执业医师证以上证件的复印件和《研究生课程班回执》寄 我院教育处。培训班限招20人。报名截至日期为2013年7月20日。 2、报到时须携带： 本人身份证原件及复印件、学历证书原件和学位证书原件及复印件、报名表、四张本人一寸近期免冠彩色照片。 3、办理交费手续： 报到当日缴纳学费20,000元整（现金、支票均可） 4、现场注册： 报到当日现场填写学生信息注册表，确认相关信息。 5、由肿瘤医院审核合格者方予录取；因使用虚假报名材料和证书而产生的一切后果由报名者自负。 七、联系方式 座机:010-8778-8817/8224 报名地址：北京市朝阳区潘家园南里17号肿瘤医院教育处 邮编：100021 中国医学科学院肿瘤医院教育处 2013年5月2日
肿瘤能量代谢重排（reprograming）与转移的关系 新陈代谢是集体生命活动的基本特征，包括物质代谢和与之相伴的能量代谢，是细胞获得能量的最重要方式。在肿瘤发生发展过程中，能量代谢常出现紊乱，造成肿瘤微环境的变化，帮助肿瘤细胞得以生存、转移及免疫逃逸。因此，能量代谢重排被认为是肿瘤的一个新的基本特征。起初能量代谢重排被认为是肿瘤细胞快速增值的结果，但是更多的新数据表明该过程可以驱动肿瘤发生并且和肿瘤干细胞的干性相关1。 普遍认为，细胞代谢，特别是肿瘤细胞的能量代谢，都依赖于有氧糖酵解的过程。通过有氧糖酵解产生的能量被认为足够以供应肿瘤细胞快速分裂，并同时允许代谢反应所需生物合成前体的积累2, 3。在一个生长的肿瘤中，适应性的代谢重编程（metabolic reprogramming），一方面是由于致癌性转化导致的，使得癌细胞获得生长优势4, 5，另一方面，快速增生癌细胞会自发性代谢重排，促进自我维持的信号转导机制，从而激发肿瘤的生长和生存5。 Venkatanarayan等人发现，敲除p63 或者p73的ΔN亚型，将上调编码与胰岛素共分泌的37个氨基酸多肽基因：IAPP的表达，导致p53缺失的肿瘤的代谢重排和退化6。他们还发现临床上用于治疗I/II型糖尿病的药物普兰林肽，可以导致p53缺失的胸腺淋巴瘤的快速退化，这为日后靶向p53缺失的肿瘤的治疗提供了参考。Jiang L等人发现, TGFβ1诱导的EMT过程，伴随着将葡萄糖转化为脂肪酸的酶类的抑制，同时细胞呼吸增强。过表达Snail1，一个调节TGFβ1诱导EMT过程中的转录因子，可以抑制ChREBP和脂肪酸合酶（FASN），这种代谢过度，抑制脂肪生成、有利于能量产生，对于TGFβ1诱导的EMT过程和肿瘤转移起到了关键的作用7。有研究发现，浸润性癌细胞通过转录共激活剂过氧
全国肿瘤登记中心负责全国肿瘤登记数据收集、质量控制、汇总、分析及发布工作。2018年2月，国家癌症中心发布了最新一期的全国癌症统计数据。由于全国肿瘤登记中心的数据一般滞后3年，本次报告发布数据为全国肿瘤登记中心收集汇总全国肿瘤登记处2014年登记资料。 报告主要发现 2014年全国恶性肿瘤估计新发病例数380.4万例（男性211.4万例，女性169.0万万例），平均每天超过1万人被确诊为癌症，每分钟有7个人被确诊为癌症。 肿瘤发病率为278.07/10万（男性为301.67/10万，女性为253.29/10万），中标率（中标率：人口标准化率按照2000年中国标准人口结构）为190.63/10万，世标率（世标率：人口标准化率按照Segi's世界标准人口结构）为186.53/10万。0-74岁累积发病率为21.58%。 胂瘤死亡率为167.89/10万，中标率为106.98/10万，世标率为106.09/10万。0-74岁累积死亡率为12.00%。 恶性肿瘤发病率由高到低依次为东部、中部、西部。调整人口结构后地区间发病率的差异缩小，但趋势并未改变。各地区中男性发病率均高于女性。 按发病例数排位，肺癌位居全国发病首位，每年发病约78.1万，其后依次为胃癌、结直肠癌、肝癌和乳腺癌。肺癌和乳腺癌分别位居男女性发病的第1位。
恶性肿瘤死亡率由高到低依次为东部、中部、西部，调整人口结构后，中部地区死亡率高于东、西部地区。各地区肿瘤年龄别死亡率趋势相似，主要恶性肿瘤死因大致相同，肺癌、肝癌、胃癌、食管癌、结直肠癌在各地区均为主要恶性肿瘤死因。 报告数据来源和质量控制 截至2017年8月30日，全国肿瘤登记中心共收集到全国31个省、自治区、直辖市的449个登记处提交的2014年肿瘤登记资料，其中县级以上城市160个，县及县级市289个。根据质量控制标准纳入339个登记处，其中东部地区140个，中部地地区112个，西部地区87个。覆盖人口共288243347人（包括男性146203891人，女性142039456人），占全国2014年年未人口数的21.07%,其中东部地区164062330人，中部地区81477272人，西部地区42703745人。 恶性肿瘤发病总体情况 据估计，2014年全国恶性肿瘤估计新发病例数380.4万例（男性211.4万例，女性169.0万万例），平均每分钟有7个人被确诊为癌症。 肿瘤发病率为278.07/10万（男性为301.67/10万，女性为253.29/10万），中标率（中标率：人口标准化率按照2000年中国标准人口结构）为190.63/10万，世标率（世标率：人口标准化率按照Segi's世界标准人口结构）为186.53/10万。0-74岁累积发病率为21.58%。胂瘤死亡率为167.89/10万，中标率为106.98/10万，世标率为106.09/10万。0-74岁累积死亡率为12.00%。
中国癌症现状及发展趋势 2014世界癌症报告、 世界卫生组织2月3日发表的 《全球癌症报告2014》中称 2012年中国新增癌症病例高居第一位 中国新增和死亡病例 世界第一 发病率低于发达国家 亚洲男性易发肺癌和肝癌 乳腺癌在全球女性中成最高发癌症 2012年新增癌症病例有近一半来之亚洲，其中大部分在中国。 肺、肝、食道、胃等4种恶性肿瘤中，中国新增病例和死亡人数均居世界首位。 2014《世界癌症报告》 2014.2.4 世界卫生组织WHO 发 布 2014《世界癌症报告》 20年后 2014.2.4 世界卫生组织WHO 发 布 2400万 中国癌症登记年报制度 2006年开始，中国肿瘤登记中心收集样本，原定每5年发布一次，后改为每年一次。 中国癌症年报 每分钟5人死于癌症 每分钟6人被确诊癌症 每7、8人中就有1人死于癌症 《2012中國腫瘤登記年報》 近20年 癌症呈现三化二线趋势 发达化 年轻化 老年化 发病率和死亡率 “二线”走高的趋势 中国癌症现状（三化二线） 中国癌症现状（三化二线） 发达化 中国人口基数庞大，因此成为世界上癌症死亡数最高的国家。 亚太地区新增癌症病人占全球45%，死亡人数占全球50% 肺癌死亡率 30年增长465% 中国癌症的整体发病率远低于美国、瑞士等发达国家， 死亡率却远高于发达国家 资料来源： 《全球癌症报告2014》 2012年国际癌症研究中心（IARC） 财经国家新闻网 中国癌症现状（三化二线） 发达化 “窮癌”發病率居高不下，“富癌”也增長迅猛，呈现此不消彼又长 中国癌症现状（三化二线） 年轻化 《2012中国肿瘤登记年报》数据显示，我国癌症发病呈现年轻化趋势，包括乳腺癌、肺癌、结肠癌、甲状腺癌等发病年龄均低于此前年龄。 比如南京最年轻的乳腺癌患者只有17岁（见图表）。 现代年轻人不良生活方式、睡眠严重不足、工作和心理压力过大，环境污染是患癌的主要因素。 中国癌症现状（三化二线） 年轻化 中国抗癌协会的统计数据显示，我国每年新发淋巴瘤患者约8.4万人，死亡人数超过4.7万人，并以每年5%的速度上升，发病人群也越来越年轻化，多见于青壮年。 因为20-40岁正是淋巴组织非常活跃的时期，高敏感性让青壮年很容易成为淋巴瘤的高危人群。 ——信息来源《光明日报》 近年来，我国年轻人患胃癌人数呈上升趋势，19-35岁的青年胃癌发病率比30年前翻了一番。由于胃癌早期并无明显症状，超过90%的胃癌病人都是在中晚期才就医的，此时5年生存率小于20%。事实上，早期胃癌的诊断率目前可达10%左右，早期治疗的治愈率也高达95%。 年轻人精力充沛、体力强，容易忽视身体的不适，也认为做胃镜检查很
中国医学科学院肿瘤医院放疗科王维虎李晔雄恶性淋巴瘤是指原发于淋巴系统的一组疾病，来源于B淋巴细胞、T淋巴细胞或自然杀伤细胞的非正常克隆性增殖，包括霍奇金淋巴瘤和非霍奇金淋巴瘤两大类。在过去十多年中，恶性淋巴瘤的研究取得了很大的进展，改变了淋巴瘤的治疗原则，从而提高了患者的疗效，改善了生存质量。 1、霍奇金淋巴瘤(Hodgkin’s lymphoma, HL) 放射治疗（简称放疗）是早期HL的根治性治疗手段。I-II期HL 扩大野单纯放疗后，10-15年总生存率为73-91%，无病生存率为75-93%。中国医学科学院肿瘤医院报道，预后好或预后不良临床I-II 期HL接受次全淋巴结照射或全淋巴结照射后，5年总生存率和无病生存率分别为94%和80%，这一结果和国外报道的大宗早期HL放疗结果相似。 对于I-II期HL患者而言，放疗后10-15年，长期的心肺并发症和第二原发肿瘤引起的死亡危险性明显高于疾病本身。因此，I-II期HL 作为一种可以治愈的疾病，近年来研究的重点转移在不降低治疗疗效的前提下，减少治疗引起的并发症。因此，开展了早期HL综合治疗的一系列随机对照研究，比较了综合治疗和单纯放疗或单纯化疗的疗效，并且研究了综合治疗时的最佳化疗方案和化疗周期数、照射野大小和照射剂量等。在放疗照射野大小方面，已经发表了4个随机分组
研究均证实：在放疗和化疗综合治疗的情况下，对于早期HL采用只包括受累区域的受累野照射可以取得和扩大野照射相同的疗效，同时降低了治疗的急性和长期毒副作用。因此，根据目前的临床研究证据，HL的合理治疗是：预后好的临床I-II期HL建议综合治疗或次全淋巴结照射，综合治疗时采用2-4周期ABVD化疗+20-30 Gy受累野照射；预后不良临床I-II期HL采用4-6周期ABVD化疗+20-40 Gy受累野照射的综合治疗，而不是单纯化疗或单纯放疗。当然，放疗治疗是I-II期HL的根治性治疗手段，如果肿瘤对化疗抗拒、病人不能耐受化疗或化疗中出现严重毒副作用时，应考虑根治性放疗。III-IV期HL患者只有化疗前肿瘤>10 cm或化疗后仍有明确肿瘤残存时才给予受累区域20-40Gy照射。 2、非霍奇金淋巴瘤(non-Hodgkin’s lymphoma, NHL) 1）单纯放射治疗可以治愈的NHL： I-II期I-II级滤泡淋巴瘤单纯放疗的10-15年无病生存率为28-53%，10-15年总生存率为43-79%，局部控制率超过90%；I-II期小淋巴细胞淋巴瘤单纯放疗后的5年生存率也大于50%，而且，目前仍不能明确化疗加入放疗后的综合治疗能否提高早期惰性淋巴瘤的生存率；I-II期结外粘膜相关淋巴组织（MALT）淋巴瘤，如胃MALT淋巴瘤对放疗敏感，并且放疗为非创伤性治疗手段，能保留胃的功能，提高生存质量，放疗合并或不合并化疗已成为I-II期胃MALT淋巴瘤的主要治疗手段之一，IE/IIE期胃
中国肿瘤现状调查 ■发病人数约占全球五分之一■死亡人数约占全球四分之一 我国目前每年新增350万癌症患者，每年癌症死亡人数达250万人，在部分城市，癌症超过了心血管疾病，成了致人于死地的“第一杀手”，癌症正越来越多地侵入人们的生活。值得注意的是，中国的癌症患者被确诊时，绝大多数已处于中晚期。癌症高发，增加的不仅仅是患者的伤痛，还给家庭社会带来沉重的经济负担。 面对如此来势汹汹的癌症病魔，人们不禁开始思考，为何我国癌症发病率居高不下？癌症发病与什么因素有关？肿瘤治疗情况究竟如何？带着一系列问题，记者去年以来深入医院、病房、研究院所、企业和有关部门采访，就肿瘤现状进行调研，试图一探究竟。 健康梦是小康梦的重要组成部分，中国亟须向肿瘤宣战。 这是一个个曾经鲜活的生命：丽蓉、罗京、晓旭、贝娜…… 这是一组触目惊心的数字：世界癌症报告估计，2012年中国癌症发病人数为3 06.5万，约占全球发病的五分之一；癌症死亡人数为220.5万，约占全球癌症死亡人数的四分之一。 健康梦是小康梦的重要组成部分。新华社记者去年以来在北京、上海、、等地走
访大量肿瘤防治专家和临床医生了解到，伴随着老龄化加剧、生态环境遭受破坏、不健康生活方式及食品安全问题凸现，我国肿瘤发病率多年持续上升，已成为一个必须高度重视的公共卫生问题乃至社会问题。 发病率、死亡率双升 在农村人眼里，癌症就是绝症。 记者走进、等在网络上被称为“癌症村”的几个村庄，村民熟悉而又害怕听到“癌症”二字。其中一个村的医务人员表示，村民患癌有年轻化趋势，四五十岁年龄段的人数在增多。 病人增多，知名肿瘤医院一床难求。北京、上海、、、这些地区的肿瘤医院“专家号一号难求”，病人往往需要排队等手术。在中国医学科学院肿瘤医院，因为床位原因，每周有700人等待入院…… 省肿瘤医院副院长葛明华从事甲状腺癌治疗，他明显感到甲状腺癌上升幅度太快了，“原先甲状腺外科医生地位不高，一年就几个病人，现在很多医院都开设了甲状腺科室”。 从全国肿瘤防治研究办公室及东、中、西部医疗专家了解到的情况和部分临床统计看，由于人口老龄化等原因，当前我国癌症发病率、死亡率呈持续增长趋势。 更为严峻的是，这种势头并未得到有效遏制。国家癌症中心肿瘤流行病学研究员代敏介绍，今后20年，我国癌症的发病数和死亡数还将持续上升：根据国际癌症研
肿瘤样钙质沉着症( tumoral calcino sis, TC) 是一种发生于大关节附近, 但并不累及关节滑膜的特发性软组织钙质沉着性疾病。TC是一种很少见的疾病, 又名瘤样钙化症、钙化性胶原溶解、臀石等。1899年由Duret首先描述,1943年由Inclan命名。本病发病原因不明, 可能与下列因素有关: 钙磷、胆固醇代谢异常; 关节附近胶原纤维对刺激所作出的反应性钙化; 遗传因素, 认为是一种常染色体显性遗传性畸形所致，与遗传相关的家族性肿瘤样钙盐沉着症（familial tumoral calcinosis，FTC）。FTC 包含2 种亚型，即分别由GALNT3 基因或SAMD9 基因突变所致，前者多伴有高磷酸血症，后者则无; 外伤因素, 为反复轻微损伤造成局部营养障碍而引起。其他的因素可能还包括红细胞生成素的升高、免疫系统功能紊乱等。TC 可发生于任何年龄, 但以10-20岁为多,女性多于男性, 家族性发病者占33%-50%。TC 多见于儿童和青少年，无明显的性别差异。目前病例报道多集中于黑色人种，在非洲和新几内亚多发，欧洲和北美洲较少。大部分患者健康情况良好，钙沉着部位可出现肿胀、疼痛、被覆皮肤溃疡、瘘管形成或局部有白垩样物质流出。 关于本病的发病机制, 目前认为, 病灶处存在大量壁菲薄、通透性高的毛细血管, 血液往复循环于其中时携来丰富的钙及磷酸根离子; 免疫组化显示病变钙化灶边缘的组织细胞样细胞源自中胚叶, 为前骨母细胞, 其主要产生碱性磷酸酶而不产生有机的骨基质。因而在局部促成大量钙质沉着, 但无骨化改变。 Slavin等按照临床表现将TC 患者分为3 种类型：（1）患者在20岁前出现多发性病变。部分患者血磷酸盐轻至中度升高，还可出现1，25 二羟基维生素D3 升高。病变多位于大关节附近，表现为皮下缓慢性生长、质地坚韧的钙化性肿块，常与其下的筋膜、肌肉或肌腱紧密相连，但不累及骨和关节。此型可认为是先天性钙代谢异常，按常染色体显性遗传，有家族发生的倾向。（2）患者发病年龄范围很大，无高磷酸盐血症，但是血清钙盐可升高。（3）病变为继发于肾功能衰竭、各型结缔组织病、进行性骨干发育异常或唐氏综合征等疾病，患者常伴有高钙血症或高磷酸血症。 病理上将TC 分为活动期和静止期, 呈多囊性或实性, 前者囊壁及间隔内衬肉芽组织, 后者仅有纤维组织和胶原纤维构成。T C 的病理特点为成纤维组织和胶原纤维组成的包膜内, 填充乳白色石灰样糊状钙化沉积物及淡黄色乳糜状液体, 囊内见大小不等的钙化灶, 囊壁可见上皮细胞和多核巨细胞。 X线检查是诊断TC的基本方法, 其表现为关节旁关节伸侧软组织中, 呈大小不一的钙化结节集结而成的分叶状团块, 呈“卵石样”，“桑葚状”，范围较广者可呈“流注状”；病变一般不累及邻近关节或骨骼。CT 与X 线平片表现一致, 但CT 对病变部位、形态及范围的显示更为全面, 能清楚显示病变与邻近关节及骨骼的关系。MRI具有多参数、多序列、多方位成像的功能, 可根据信号判断组织成分; 由于肿瘤主要由纤维包膜包裹的钙化沉积物及淡黄色乳糜状液体组成, 内有纤维间隔,因此T1WI 肿瘤呈不均匀低信号, T2WI 呈不均匀高信号; 肿瘤包膜呈长T1 、长T2信号。MRI对观察肿瘤边缘及肿瘤与关节、骨骼的关系价值大, 能多方位显示病变不累及关节或骨骼, 对诊断有较大帮助。 肿瘤样钙质沉着症是由于多部位的羟磷灰石结晶组成的以关节周围钙化的软组织肿块为特征性的疾病、多数与磷酸过高所致的异常磷酸盐代谢有关，通常发生于肩髋等大关节。特发性肿瘤样钙质沉着症有家庭倾向，多见于肾病患者，继发性钙质沉着症的鉴别诊断，包括骨肉瘤、软骨肉瘤及滑膜肉瘤的软组织钙化和骨化，也包括良性软组织肿块中的营养不良和代谢所致的钙化或骨化，也可伴随临近的骨侵蚀，但硬皮病易累及手部，而肿瘤样钙质沉着症的特征性X线表现，即在肿块中发现不规则分叶状肿块被纤维分隔，形如鹅卵石或“鸡笼”样表现。但其他疾病，如硬皮病的肿块亦呈分叶状，导致了肿瘤样钙质沉着症与其他疾病鉴别上的困难。 本病的治疗方法是彻底切除病灶, 特别是彻底刮除位于松质骨内的钙化物质, 以防术后
营养与疾病的关系 姓名：何仕丹学号：1324310035 专业：药物制剂年级：2013级 随着社会经济、文化和科学技术的发展，人们饮食结构发生变化，营养性疾病对人类健康的影响愈来愈明显，许多疾病的营养因素更加明确，如何防制营养性疾病就成为保护人类健康的重要内容。营养性疾病是指因营养素供给不足、过多或比例失调而引起的一系列疾病的总称。主要包括营养缺乏病、营养过多症（或中毒）、营养代谢障碍性疾病和以营养为主要病因的一些慢性退行性疾病等。这些疾病有的与营养有直接因果关系；有的虽与营养没有直接因果关系，但有明显的相关性，如心血管疾病、肥胖症、糖尿病及某些肿瘤等。 一、营养与疾病 (一)营养缺乏或不足 营养缺乏可直接引起相应的营养缺乏病，如蛋白质——热能营养不良、脚气病、坏血病、营养性贫血等。引起营养缺乏病的原因常分为原发性和继发性两类。 1. 原发性营养缺乏，造成营养素摄入不足的常见的原因，一是战争、灾荒、贫困等社会经济因素引起的食物短缺；二是不良的饮食习惯，如偏食、忌食或挑食等使某些食物摄入不足或缺乏而引起营养缺乏；三是不合理的烹调加工，造成食物中营养素破坏和损失，虽摄入食物数量不少，但某些营养素却不足。。 2. 继发性营养缺乏由于机体内外各种因素影响而引起营养缺乏或不足，主要是疾病、药物、生理变比等原因引起的消化、吸收、利用障碍或需要量增加等。 (二)营养过剩或比例失调 维生素A、D及某些必需微量元素摄入过多可致中毒；热能、脂肪等摄入过多可致肥胖、高血脂症、动脉粥样硬化等；高盐和低纤维素膳食可引起高血压等。大量研究表明、营养过剩不仅是人群中某些慢性疾病发病率增高的因素，而且还和某些肿瘤，如结肠癌、乳腺癌、胃癌等有明显关系。造成营养过剩或比例失调的主要原因是： 1. 膳食结构不合理膳； 2. 不良的饮食行为和习惯 二、常见的营养性疾病 (一)营养不良常见疾病 1. 蛋白质——热能营养不良（PEM）常见于儿童和婴幼儿，严重时可影响生长发育及智力发育，病儿由于抵抗力低下，易受感染，死亡率高。 原发性蛋白质——热能营养不良是由于长期蛋白质、热能摄入不足，常见于缺乏喂养知识，喂食过少，不添加辅助食品，母乳不足，早产儿先天不足。 继发性蛋白质——热能营养不良，多由于慢性胃炎、肠炎、消化不良、腹泻等原因使营养素消化吸收障碍；或由于长期发烧、慢性消耗性疾病而营养素未能及时补充；或长期患有妨碍进食或食欲不振的疾病等。 2. 维生素A缺乏症临床表现主要是夜盲症与干眼病。由于视黄醇供给不足，体内视紫红质合成不足，早期出现暗适应时间延长，严重时出现夜盲症。 3. 维生素C缺乏症冬、春季节由于蔬菜水果供应不足，食物品种单调，维生素C缺乏症常可发生。人体由于缺乏L—古乐糖酸氧化酶，不能合成维生素C，而人体内贮存量又很少，食品在加工、贮运和烹调中丢失维生素C严重，主要临床表现有皮肤、粘膜出血倾向，如皮肤出血点、瘀斑，或鼻、月经过多、牙龈出血，严重时可有内脏出血等。此外还表现有牙龈肿胀、牙齿松动、骨骼发育不良、骨骼疼痛、毛囊角化过度等。 4. 维生素B1缺乏症长期发烧、慢性消耗性疾病、代谢旺盛性疾病、烧伤病人也可出现维生素B1缺乏症。典型临床表现叫脚气病，可分为湿性脚气病和干性脚气病两型，前者以心功能不全表现为主，后
1. 在诸多诱发肿瘤的病因中，如何认识遗传因素的作用？请指出遗传因素在肿瘤发生过程中的主要作用！ 2. 什么证据可以证明体细胞突变是启动癌变的主要原因？ 3. 简述“两次打击学说”，两次打击的主要内容？ 4. 软琼脂 正常未转化的细胞在培养基内增长至某种饱和密度时，即出现停止生长，这称为接触抑制。与此相反，高度转化的细胞则失去接触抑制，它们可以继续高密度生长，甚至出现多层次的特性，直至它们耗尽培养液中的营养物为止。目前常使用双层软琼脂检测法，上层琼脂中含有细胞，因琼脂为半流体，细胞悬浮于琼脂中不下沉，如果细胞分散和混合良好，则细胞被均匀互相隔离，因两层琼脂中都含有DMEM（细胞培养基），细胞可充分营养进行增殖生长。由于细胞被相互隔离，孤立存在，消除了细胞相互影响，对细胞依存性大的细胞增殖生长不利，肿瘤细胞独立性强，失去接触抑制性，仍能形成克隆。软琼脂集落形成实验是当前检测肿瘤细胞生物性能最为常用的方法，与细胞恶性程度有很大的符合率。 5. 裸鼠原理？ 1. 简述在对人类肿瘤研究中，裸鼠致瘤实验的基本原理和意义； 基本原理：由于裸鼠先天性胸腺缺乏，细胞免疫缺陷，故可接受同种或异种的正常及恶性组织移植。将一定量的肿瘤组织或细胞移植于裸鼠皮下，可在裸鼠体内生长，建立移植性人类肿瘤模型。 意义：裸鼠致瘤实验是检测恶性转化细胞的一个有力的生物学指标。大量实验证明，人类恶性肿瘤的裸鼠移植后，在病理形态、生化代谢、染色体模型、细胞动力学等方面与移植前相同，因而是肿瘤实验研究中的一种理想模型。该模型对于在活体状态下研究肿瘤的发生、发展、各种生物学特性及筛选有效抗癌药方面都将是极为有用的。 6. 简述C基本结构？ 细胞是所有生物体的基本单位。 原核细胞：细菌、立克次体及支原体等
细胞代谢的改变是肿瘤的重要特征之一。大量研究发现肿瘤细胞发生了代谢重编程，并且对肿瘤代谢的认识已经不再局限于糖酵解和三羧酸循环的改变，诸多代谢通路包括脂肪酸代谢、胆固醇代谢、谷氨酰胺代谢、丝氨酸代谢、一碳单位代谢、胆碱代谢等，在肿瘤细胞中均发生了重编程变化。随着肿瘤生物学研究的不断深入，细胞代谢异常在肿瘤发生发展中的作用研究已成为活跃的国际学术前沿，细胞代谢异常先于肿瘤发生的理论也逐步在研究中得到了证实。近年来，研究发现葡萄糖缺乏可促进KRAS野生型的细胞获得KRAS及其信号通路分子的突变，首次证明细胞代谢异常可以导致原癌基因突变。2-HG竞争性抑制多种α-KG依赖的双加氧酶活性（如：介导DNA氧化去甲基化的Tet双加氧酶），以及其他表观遗传调控相关的酶（如：组蛋白去甲基化酶）等，从而影响表观遗传调控，启动肿瘤的发生、影响肿瘤的进展。这些研究发现提供了代谢改变可以促进肿瘤发生的直接证据，而且其调控的关键节点也正在成为肿瘤诊断和治疗中潜在的靶点。基于肿瘤代谢改变的研究成果，将为肿瘤的分子诊断、精确分型、预后分析、靶向治疗和药物反应性等提供重要的理论指导。 肿瘤代谢改变与肿瘤发生发展之间的关系涉及复杂的生物学过程和多种分子机制，而代谢物及细胞感受代谢物异常在其中的作用日益受到关注。例如:代谢产物乳酸可以直接增加某些蛋白的稳定性，从而促进细胞增殖和血管新生；肿瘤细胞能感受环境代谢物变化，增加肿瘤侵袭转移相关蛋白的合成；肿瘤细胞还能调整自身的能量感受通路，增强对代谢压力的适应，提高在低营养状态下的存活率，是肿瘤产生抗药性的因素之一。此外，肿瘤细胞还通过与免疫细胞竞争营养，而抑制抗肿瘤免疫，如：肿瘤细胞糖酵解增高可以引起肿瘤微环境中T细胞营养不良，抑制T细胞肿瘤免疫；调控胆固醇代谢途径可提高肿瘤特异的细胞毒T细胞的活性，增强抗肿瘤细胞免疫。肿瘤代谢研究的领域已进一步扩展到肿瘤微环境，以及对肿瘤免疫的影响。因此，发现代谢物异常、了解细胞如何感受代谢物异常、代谢异常对细胞的恶性转化作用以及对肿瘤免疫微环境的改造等是重要的前沿科学问题，阐明其内在的分子机制将为肿瘤预防、早期诊断和治疗提供新思路。 本立项拟以发现与肿瘤发生相关的代谢物为切入点，研究重要代谢物异常在细胞恶性转化中的作用及其分子机制；明确细胞感受代谢物失调的机制及其在肿瘤发生发展中的意义；探索代谢异常对肿瘤微环境的改造及其生物学效应和机制。从而阐释代谢异常在肿瘤细胞及其微环境的基因表达与信号转导中的作用和地位，深入理解代谢物（或包括相关代谢酶）和细胞感受代谢物失调在肿瘤发生发展中的功能与机制，为临床转化提供新的诊断靶标与治疗靶点。本项目的实施对促进代谢生物学、化学、免疫学与肿瘤学基础和临床研究的学科交叉，具有重要的意义。 一、科学目标 以我国常见高发的1-2种肿瘤为模型，发现一批在肿瘤发生发展中有明确调控作用的重要代谢物，研究这些代谢物异常在细胞恶性转化中的作用及其机制,确定代谢物和细胞相互作用失调在肿瘤发生中的作用与机制，解析代谢物对肿瘤细胞信号转导与基因表达的调控功能，阐明代谢异常对肿瘤微环境的改造及其生物学效应，建立适于转化研究的代谢物体外及体内研究的实验平台，发现可能用于肿瘤临床诊断的代谢物分子标记物，鉴定可能具有肿瘤临床治疗前景的代谢物分子靶标。 二、研究内容 选择我国常见高发的1-2种肿瘤为模型，开展如下四方面的研究： （一）肿瘤相关代谢物的发现：采用高通量代谢组学、蛋白组学和生物信息学等检测手段，发现、筛选和鉴定一批与肿瘤表型特征密切相关的代谢物；运用细胞模型、荷瘤小鼠及转基因小鼠等动物模型，证实其体内外对正常细胞的恶性转化作用。
髓内肿瘤和髓外肿瘤的判断和定位(图/文) (2011-01-13 23:49:36) 脊髓内肿瘤和脊髓外肿瘤不是一个少见病，临床工作中常需根据患者的痛温觉的进展变化去区别是髓内还是髓外肿瘤。 学好基础解剖就一清二楚了。 图1 脊髓横断面模式图图2 脊髓横切面示意图
从图1中 可以看到，位于 脊髓白质外侧 索的前半和前 索中有一组纤 维束叫脊髓丘 脑束，是专门传 导人体痛温觉 和粗略触觉冲 动的，向颅侧经 脑干止于背侧 丘脑（见图3）。 从图3可 以看到，躯干 四肢的痛温 觉从皮肤感受 器-→经传入神 经-→同侧脊髓 后角的固有神 经核-→上升 1-2个节段（或 边上升边交叉 到对侧）-→经 前连合-→对侧 侧索形成脊髓 丘脑束-→上行 止于丘脑外侧 核-→由此处的 第三神经元发 出纤维经内囊 后肢丘脑辐射 上升-→到大脑 皮质中央后回 的感觉区，从而感知痛温觉。 从图2中可知，脊髓丘脑束内的纤维排列是有定位规律的，从内至外分别是颈胸腰骶（CTLS），所以，当为脊髓外肿瘤时，肿瘤对脊髓的压迫首先是出现骶腰神经分布区的痛温觉障碍，并随肿瘤的发展逐步影响到胸和颈，也就是说痛温觉障碍的进展是自病变节段由下向上发展。相反，当为髓内肿瘤时，痛温觉障碍的进展是自病变节段由上向下发展。 肿瘤的定位：肿瘤位于痛温觉缺陷平面上升1-2个脊髓节段的对侧，因为痛温觉障碍的平面是反映在肿瘤向下1-2个脊髓节段的对侧。比如一患者感觉左侧脐部（为T10平面）痛温觉障碍并逐渐向上发展，
说明肿瘤为髓外肿瘤，而且位于右侧胸髓8平面,根据脊髓与椎管的对 应关系定位于胸椎6-7的椎管内右侧的脊髓 外。图3 痛温觉传导通路
国家癌症中心全国癌症 报告 Company number【1089WT-1898YT-1W8CB-9UUT-92108】
全国肿瘤登记中心负责全国肿瘤登记数据收集、质量控制、汇总、分析及发布工作。2018年2月，国家癌症中心发布了最新一期的全国癌症统计数据。由于全国肿瘤登记中心的数据一般滞后3年，本次报告发布数据为全国肿瘤登记中心收集汇总全国肿瘤登记处2014年登记资料。 报告主要发现 2014年全国恶性肿瘤估计新发病例数380.4万例（男性211.4万例，女性169.0万万例），平均每天超过1万人被确诊为癌症，每分钟有7个人被确诊为癌症。 肿瘤发病率为278.07/10万（男性为301.67/10万，女性为 253.29/10万），中标率（中标率：人口标准化率按照2000年中国标准人口结构）为190.63/10万，世标率（世标率：人口标准化率按照 Segi's世界标准人口结构）为186.53/10万。0-74岁累积发病率为21.58%。 胂瘤死亡率为167.89/10万，中标率为106.98/10万，世标率为106.09/10万。0-74岁累积死亡率为12.00%。 恶性肿瘤发病率由高到低依次为东部、中部、西部。调整人口结构后地区间发病率的差异缩小，但趋势并未改变。各地区中男性发病率均高于女性。
按发病例数排位，肺癌位居全国发病首位，每年发病约78.1万，其后依次为胃癌、结直肠癌、肝癌和乳腺癌。肺癌和乳腺癌分别位居男女性发病的第1位。 恶性肿瘤死亡率由高到低依次为东部、中部、西部，调整人口结构后，中部地区死亡率高于东、西部地区。各地区肿瘤年龄别死亡率趋势相似，主要恶性肿瘤死因大致相同，肺癌、肝癌、胃癌、食管癌、结直肠癌在各地区均为主要恶性肿瘤死因。 报告数据来源和质量控制 截至2017年8月30日，全国肿瘤登记中心共收集到全国31个省、自治区、直辖市的449个登记处提交的2014年肿瘤登记资料，其中县级以上城市160个，县及县级市289个。根据质量控制标准纳入339个登记处，其中东部地区140个，中部地地区112个，西部地区87个。覆盖人口共288243347人（包括男性146203891人，女性142039456人），占全国2014年年未人口数的21.07%,其中东部地区164062330人，中部地区81477272人，西部地区42703745人。 恶性肿瘤发病总体情况 据估计，2014年全国恶性肿瘤估计新发病例数380.4万例（男性211.4万例，女性169.0万万例），平均每分钟有7个人被确诊为癌症。