Preparing the "soil": The primary tumor induces vasculature reorganization in the sentinel lymph node before the arrival of metastatic cancer cells
ABSTRACT Sentinel lymph node (SLN) metastasis is the first step in the spreading of cancer in many malignancies. Tumor-reactive lymphadenopathy in SLNs has been observed for decades, but alterations of the lymphatic channels and vasculature in these nodes before the arrival of metastatic tumor cells remain unexplored. Using animal models, we show here that, before the establishment of metastasis in the SLN, there are reorganizations of the lymphatic channels and the vasculature. The node becomes a functional blood vessel-enriched and lymph vessel/sinus-enriched organ before metastasis. The enlargement of the lymph sinuses is correlated with the primary tumor weight. The newly emerged functional blood vessels develop from high endothelial venules (HEV), in which the proliferation rate of the endothelial cells is also significantly increased. Similar alterations of the HEVs are also characterized in the axillary lymph nodes from human breast cancer patients without the evidence of metastasis. These findings support the hypothesis that modification of the microenvironment for a secondary tumor (i.e., vasculature reorganization in the SLN) can be initiated by a primary tumor before and independent of the physical presence of metastatic cancer cells.
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- "These methods have limited sensitivity, because relatively large anatomical sizes are required for reliable detection (Winnard et al. 2008). In addition, current imaging approaches to evaluate lymph node metastasis mainly rely on the size and the shape of the involved lymph node (Qian et al. 2006). However, nodal metastases are often microscopic, so neither computed tomography (CT) nor standard magnetic resonance (MR) imaging can rule them out reliably (Eiber et al. 2010). "
ABSTRACT: Lymphangiogenesis in tumor-draining lymph nodes (LNs) starts before the onset of metastasis and is associated with metastasis to distant LNs and organs. In this study, we aimed to visualize tumor-induced lymphangiogenesis with a tumor lymphatics-specific peptide LyP-1. The LyP-1 peptide was labeled with a near-infrared fluorophore (Cy5.5) for optical imaging. At days 3, 7, 14 and 21 after subcutaneous 4T1 tumor inoculation, Cy5.5-LyP-1 was administered through the middle phalanges of the upper extremities of the tumor-bearing mice. At 45 min and 24 h postinjection, brachial LN fluorescence imaging was performed. Ex vivo fluorescence images were acquired for quantitative analysis of the fluorescence intensity. Tumor-induced lymphangiogenesis was confirmed by LYVE-1 immunostaining and increased size of tumor side brachial LNs. Cy5.5-LyP-1 staining in LNs co-localized with LYVE-1, suggesting lymphatics-specific binding of LyP-1 peptide. The brachial LNs were clearly visualized by optical imaging at both time points. The tumor side LNs showed significantly higher fluorescence intensities than the contralateral brachial LNs at days 7, 14, and 21, but not day 3 after tumor inoculation. At day 21 after tumor inoculation, the average signal of tumor-draining LNs was 78.0±2.44, 24.3±5.43, 25.6±0.25 (×10(3) photon/cm2/s) using Cy5.5-LyP-1, Cy5.5-LyP-1 with blocking, and Cy5.5 only, respectively. Tumor-draining brachial LNs showed extensive growth of lymphatic sinuses throughout the cortex and medulla. Use of LyP-1 based imaging probes with optical imaging offers a useful tool for the study of tumor-induced lymphangiogenesis. LyP-1 may serve as a marker of lymphangiogenesis useful in detecting "high risk" LNs before tumor metastasis and after micro-metastasis, as well as for screening potential anti-lymphatic therapies.Amino Acids 07/2011; 42(6):2343-51. DOI:10.1007/s00726-011-0976-1 · 3.65 Impact Factor
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- "Human nasopharyngeal carcinoma cell lines CNE-2 and SUNE-1 were maintained in DMEM containing 10% fetal bovine serum and maintained in a humidified atmosphere with 5% CO 2 at 37 °C. S16, a cisplatin-sensitive subclone derived from CNE-2, was isolated by limited dilution as previously described (Qian et al., 2006) and was maintained similarly as the parental CNE-2 cells. "
ABSTRACT: Translational control at the initiation step has been recognized as a major and important regulatory mechanism of gene expression. Eukaryotic initiation factor-3a (eIF3a), a putative subunit of the eIF3 complex, has recently been shown to have an important role in regulating the translation of a subset of mRNAs and is found to correlate with the prognosis of cancers. In this study, using nasopharyngeal carcinoma (NPC) cells as a model system, we tested the hypothesis that eIF3a negatively regulates the synthesis of nucleotide excision repair (NER) proteins, and, in turn, cellular response to treatments with DNA-damaging agents such as cisplatin (cis-dichlorodiammine platinum(II) (CDDP)). We found that a CDDP-sensitive sub-clone S16 isolated through limited dilution from an NPC cell line CNE-2 has increased eIF3a expression. Knocking down its expression in S16 cells increased cellular resistance to CDDP, NER activity and synthesis of the NER proteins XPA, XPC, RAD23B and RPA32. Altering eIF3a expression also changed the cellular response to CDDP and UV treatment in other NPC cell lines. Taken together, we conclude that eIF3a has an important role in the CDDP response and in NER activity of NPCs by suppressing the synthesis of NER proteins.Oncogene 05/2011; 30(48):4814-23. DOI:10.1038/onc.2011.189 · 8.56 Impact Factor
- "Tumor cell intravasation occurs in association with perivascular macrophages . Specialized cells of bone marrow, lymph nodes and lungs take part in formation of the pre-metastatic niche   . Cytokines in the hematopoietic microenvironment facilitate leukemic proliferation . "
Article: Cancer: Shift of the paradigm[Show abstract] [Hide abstract]
ABSTRACT: Cancer is usually considered to be a by-product of design limitations of a multicellular organism and its intrinsic fallibility. However, recent data prompt a revision of some established notions about carcinogenesis and form a new paradigm of carcinogenesis as a highly conserved biological phenomenon - a programmed death of an organism. This altruistic program, which is unleashed when mutagenesis surpasses a certain critical threshold, gives a population the important benefit acting as a guardian of the gene pool against the spread of certain mutant genes. A growing body of evidence supports this point of view: (i) epigenetic changes leading to cancer arise early, simultaneously in many cells and look like deterministic regulation; (ii) concept of cancer stem cell suggests a view of carcinogenesis not as vague transformation but as well known differentiation; (iii) tumor/host relations usually perceived as antagonistic are, in reality, synergistic; (iv) death of an individual from cancer is predetermined and results apparently from a specific activity (killer function) of cancer cell and (v) evolutionary conservation indicates that cancer comes with a general advantage that explains its evolutionary success. A holistic approach to carcinogenesis suggests new avenues of research and new therapeutic strategy.Medical Hypotheses 09/2008; 71(6):839-50. DOI:10.1016/j.mehy.2008.07.041 · 1.07 Impact Factor