Malignant melanoma is one of the most aggressive malignancies in humans and is responsible for 60-80% of deaths from skin cancers. The 5-year survival of patients with metastatic malignant melanoma ...is about 14%. Its incidence has been increasing in the white population over the past two decades. The mechanisms leading to malignant transformation of melanocytes and melanocytic lesions are poorly understood. In developing malignant melanoma, there is a complex interaction of environmental and endogenous (genetic) factors, including: dysregulation of cell proliferation, programmed cell death (apoptosis) and cell-to-cell interactions. The understanding of genetic alterations in signalling pathways of primary and metastatic malignant melanoma and their interactions may lead to therapeutics modalities, including targeted therapies, particularly in advanced melanomas that have high mortality rates and are often resistant to chemotherapy and radiotherapy. Our knowledge regarding the molecular biology of malignant melanoma has been expanding. Even though several genes involved in melanocyte development may also be associated with melanoma cell development, it is still unclear how a normal melanocyte becomes a melanoma cell. This article reviews the molecular events and recent findings associated with malignant melanoma.
Endobronchial implantation of NCI-H460 cells into the nude rat generates a primary lung tumor with mediastinal lymph node spread, but rarely systemic metastases. We isolated tumor cells from ...mediastinal nodes, orthotopically reimplanted the cells into nude rats and repeated this four times to derive a cell line, designated H460SM, that spontaneously metastasizes to bone, kidney, brain, soft tissue and contralateral lung. H460SM cells demonstrated higher invasive activity in vitro than parental NCI-H460 cells. Spectral karyotyping revealed a new inversion within 17q and loss of an extra normal copy of chromosome 14 present in parental NCI-H460 cells. Expression profiling of orthotopic primary tumors revealed differential expression of 360 genes. Of these, 173 were represented in the probe set of a 19.2K OCI cDNA microarray previously used to profile the gene expression of surgically resected lung cancer specimens. We have computationally validated clinical importance of these genes by using in silico analysis of 18 cases of pulmonary adenocarcinoma, which were split into two patient groups with markedly different clinical outcome. The model identifies additional novel candidate genes for the progression of lung cancer to systemic metastases and poor prognosis.
The receptor for the type 1 insulin-like growth factor (IGF-I) has been implicated in cellular transformation and the acquisition of an invasive/metastatic phenotype in various tumors. Following ...ligand binding, the IGF-I receptor is internalized, and the receptor.ligand complex dissociates as the ligand is degraded by endosomal proteinases. In the present study we show that the inhibition of endosomal IGF-I-degrading enzymes in human breast and murine lung carcinoma cells by the cysteine proteinase inhibitors, E-64 and CA074-methyl ester, profoundly altered receptor trafficking and signaling. In treated cells, intracellular ligand degradation was blocked, and although the receptor and two substrates, Shc and Insulin receptor substrate, were hyperphosphorylated on tyrosine, IGF-I-induced DNA synthesis, anchorage-independent growth, and matrix metalloproteinase synthesis were inhibited. The results suggest that ligand processing by endosomal proteinases is a key step in receptor signaling and function and a potential target for therapy.
Polarimetric second-harmonic generation (P-SHG) microscopy is used to quantify the structural alteration of collagen in stage-I,-II and -III non-small cell lung carcinoma (NSCLC)
tissue. The achiral ...and chiral molecular second-order susceptibility tensor components ratios (
and
, respectively), the degree of linear polarization (
) and the in-plane collagen fiber orientation (
) were extracted. Further, texture analysis was performed on the SHG intensity,
,
,
and
. The distributions of
,
,
and
as well as the textural features of entropy, correlation and contrast show significant differences between normal and tumor tissues.
Polarization second harmonic microscopy was used for collagen imaging in human non-small cell lung carcinoma and normal lung tissues ex vivo and revealed significant differences in the nonlinear ...susceptibility component ratio, demonstrating potential use in cancer diagnosis.
Using integrative genomics and functional screening, we identified coiled-coil domain containing 68 (CCDC68) as a novel putative tumor suppressor gene (TSG) in pancreatic ductal adenocarcinoma ...(PDAC). CCDC68 allelic losses were documented in 48% of primary PDAC patient tumors, 50% of PDAC cell lines and 30% of primary patient derived xenografts. We also discovered a single nucleotide polymorphism (SNP) variant (SNP rs1344011) that leads to exon skipping and generation of an unstable protein isoform CCDC68Δ(69-114) in 31% of PDAC patients. Overexpression of full length CCDC68 (CCDC68(wt)) in PANC-1 and Hs.766T PDAC cell lines lacking CDCC68 expression decreased proliferation and tumorigenicity in scid mice. In contrast, the downregulation of endogenous CCDC68 in MIAPaca-2 cells increased tumor growth rate. These effects were not observed with the deletion-containing isoform, CCDC68Δ(69-114).
We employ wide‐field second harmonic generation (SHG) microscopy together with nonlinear Stokes polarimetry for quick ultrastructural investigation of large sample areas (700 μm × 700 μm) in thin ...histology sections. The Stokes vector components for SHG are obtained from the polarimetric measurements with incident and outgoing linear and circular polarization states. The Stokes components are used to construct the images of polarimetric parameters and deduce the maps of ultrastructural parameters of achiral and chiral nonlinear susceptibility tensor components ratios and cylindrical axis orientation in fibrillar materials. The large area imaging was employed for lung tumor margin investigations. The imaging shows reduced SHG intensity, increased achiral susceptibility ratio values, and preferential orientation of collagen strands along the boarder of tumor margin. The wide‐field Stokes polarimetric SHG microscopy opens a possibility of quick large area imaging of ultrastructural parameters of tissue collagen, which can be used for nonlinear histopathology investigations.
We employ wide‐field second harmonic generation (SHG) microscopy together with nonlinear Stokes polarimetry for quick ultrastructural investigation of large sample areas in thin histology sections. Wide‐field Stokes polarimetric SHG microscopy opens a possibility of quick large area imaging of ultrastructural parameters of tissue collagen, which can be used for nonlinear histopathology investigations.
Fibroblast activation protein (FAP) is a cell-surface serine protease highly expressed on cancer-associated fibroblasts of human epithelial carcinomas but not on normal fibroblasts, normal tissues, ...and cancer cells. We report herein a novel FAP-triggered photodynamic molecular beacon (FAP-PPB) comprising a fluorescent photosensitizer and a black hole quencher 3 linked by a peptide sequence (TSGPNQEQK) specific to FAP. FAP-PPB was effectively cleaved by both human FAP and murine FAP. By use of the HEK293 transfected cells (HEK-mFAP, FAP+; HEK-vector, FAP−), systematic in vitro and in vivo experiments validated the FAP-specific activation of FAP-PPB in cancer cells and mouse xenografts, respectively. FAP-PPB was cleaved by FAP, allowing fluorescence restoration in FAP-expressing cells while leaving non-expressing FAP cells undetectable. Moreover, FAP-PPB showed FAP-specific photocytotoxicity toward HEK-mFAP cells whereas it was non-cytotoxic toward HEK-Vector cells. This study suggests that the FAP-PPB is a potentially useful tool for epithelial cancer detection and treatment.
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