Fluorescence as a Concept in Colorectal Lymph Node Diagnosis

Moesta, K. T.; Ebert, Bernd; Handke, T.; Rinneberg, H.; Schlag, Peter M.

doi:10.1007/978-3-642-57151-0_26

“…As far as we know, this is the first report, either experimental or clinical, that PPIX fluorescence induced by exogenous administration of 5-ALA is effective in the diagnosis of LN metastases of digestive organ cancer, although metastatic LNs of human colorectal cancer could be distinguished by using the properties of endogenous porphyrin-based fluorescence. 35 With the use of the difference between the accumulation of PPIX after 5-ALA administration in tumor tissues and in normal lymphatic tissues, metastatic foci could easily be detected by fluorescence stereomicroscopy.…”

Section: Discussionmentioning

confidence: 99%

Precise detection of lymph node metastases in mouse rectal cancer by using 5‐aminolevulinic acid

Murayama

¹

,

Harada

²

,

Imaizumi

³

et al. 2009

Intl Journal of Cancer

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Accurate diagnosis of metastatic lymph nodes (LNs) is essential in choosing appropriate treatment for gastrointestinal carcinoma. Our aim was to evaluate the diagnostic power of 5-aminolevulinic acid (5-ALA) for LN metastasis in mouse rectal cancer. Colorectal cancer cell lines, isolated cells from normal LNs, and orthotopic mouse model incorporating enhanced green fluorescent proteintagged and untagged human rectal cancer cells were studied after 5-ALA administration by using confocal microscopy, fluorescence stereomicroscopy, fluorescence lifetime imaging microscopy (FLIM), multichannel spectrophotometry and macroconfocal imaging system to precisely detect LN metastases. In vitro confocal microscopic analyses showed that all colorectal cancer cell lines tested were positive for 5-ALA-induced fluorescence, whereas isolated normal LN cells were negative. 5-ALA-induced protoporphyrin IX (PPIX) fluorescence, verified by FLIM and multichannel spectrophotometry, revealed LN metastases in mice-bearing human rectal cancer cells. Occult LN metastases, unrecognized on white-light imaging and simplified hematoxylin-eosin analyses, were readily detectable on 5-ALA-induced PPIX fluorescence imaging. In vivo macroconfocal images clearly revealed PPIX-fluorescence-positive cancer cells in draining lymph vessels and nodes. Together with specific speckled patterns of PPIX-fluorescence in metastatic lesions, the PPIX-fluorescence intensity ratio of metastatic and nonmetastatic lesions discriminated metastasis with 100% sensitivity and 100% specificity in excised whole LN samples. These results show that fluorescence diagnosis with 5-ALA is very accurate in the detection of LN micrometastases of mouse rectal cancer, suggesting that this feasible diagnostic approach is applicable to target sectioning of metastases of resected fresh whole node samples in pathology laboratories. ' UICCKey words: lymph node metastasis; rectal cancer; 5-aminolevulinic acid; fluorescence lifetime imaging microscopy; macroconfocal imaging Colorectal cancer is the second most frequent malignant tumor encountered in developed countries. 1,2 Lymph node (LN) metastasis is a common feature of metastasis associated with advanced colorectal cancer and serves as an important prognostic indicator for patients with colorectal cancer. 3,4 Accurate diagnosis of LN metastasis is essential for designing therapeutic strategies and assessing outcomes of patients.Computed tomography (CT) and magnetic resonance imaging are commonly used modalities capable of detecting LN metastasis of colorectal cancer. It is well known that the sensitivity of these methods in detecting metastatic nodes is up to about 67% 5-7 because the diagnostic criterion for LN metastasis by using these modalities is principally based on their size. Fluorodeoxyglucosepositron emission tomography (FDG-PET) is also an effective tool for detecting malignant disease, which takes advantage of the difference in glucose metabolism. 8,9 However, the diagnostic sensitivity of FDG-PET for metastatic LN from...

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“…We looked for evidence of porphyrin overdrive, defined by the non-homeostatic, imbalanced heme biosynthetic pathways and heightened accumulation of heme pathway intermediates. As existing literature predominantly identifies PPIX as the major accumulated form in both in vitro and in vivo settings ( Szeimies et al, 1995 ; Moesta et al, 2001 ; Bellini et al, 2008 ; Kaneko & Kaneko, 2016 ), in this study, we refer to PPIX as the representative porphyrin species. Future studies will conduct a more detailed biochemical analysis to identify specific heme intermediate forms in different cancer cell types.…”

Section: Resultsmentioning

confidence: 99%

Porphyrin overdrive rewires cancer cell metabolism

Adapa,

Hunter,

Amin

et al. 2024

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All cancer cells reprogram metabolism to support aberrant growth. Here, we report that cancer cells employ and depend on imbalanced and dynamic heme metabolic pathways, to accumulate heme intermediates, that is, porphyrins. We coined this essential metabolic rewiring “porphyrin overdrive” and determined that it is cancer-essential and cancer-specific. Among the major drivers are genes encoding mid-step enzymes governing the production of heme intermediates. CRISPR/Cas9 editing to engineer leukemia cell lines with impaired heme biosynthetic steps confirmed our whole-genome data analyses that porphyrin overdrive is linked to oncogenic states and cellular differentiation. Although porphyrin overdrive is absent in differentiated cells or somatic stem cells, it is present in patient-derived tumor progenitor cells, demonstrated by single-cell RNAseq, and in early embryogenesis. In conclusion, we identified a dependence of cancer cells on non-homeostatic heme metabolism, and we targeted this cancer metabolic vulnerability with a novel “bait-and-kill” strategy to eradicate malignant cells.

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“…In this study, we demonstrated that 5‐ALA is a sensitive probe for detection of LN metastasis in a murine model of rectal cancer and that its diagnostic accuracy is extremely high. As far as we know, this is the first report, either experimental or clinical, that PPIX fluorescence induced by exogenous administration of 5‐ALA is effective in the diagnosis of LN metastases of digestive organ cancer, although metastatic LNs of human colorectal cancer could be distinguished by using the properties of endogenous porphyrin‐based fluorescence 35. With the use of the difference between the accumulation of PPIX after 5‐ALA administration in tumor tissues and in normal lymphatic tissues, metastatic foci could easily be detected by fluorescence stereomicroscopy.…”

Section: Discussionmentioning

confidence: 94%

Attorney stresses importance of patents in fostering innovation

Printz¹

2009

Cancer

0

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Accurate diagnosis of metastatic lymph nodes (LNs) is essential in choosing appropriate treatment for gastrointestinal carcinoma. Our aim was to evaluate the diagnostic power of 5‐aminolevulinic acid (5‐ALA) for LN metastasis in mouse rectal cancer. Colorectal cancer cell lines, isolated cells from normal LNs, and orthotopic mouse model incorporating enhanced green fluorescent protein‐tagged and untagged human rectal cancer cells were studied after 5‐ALA administration by using confocal microscopy, fluorescence stereomicroscopy, fluorescence lifetime imaging microscopy (FLIM), multichannel spectrophotometry and macroconfocal imaging system to precisely detect LN metastases. In vitro confocal microscopic analyses showed that all colorectal cancer cell lines tested were positive for 5‐ALA‐induced fluorescence, whereas isolated normal LN cells were negative. 5‐ALA‐induced protoporphyrin IX (PPIX) fluorescence, verified by FLIM and multichannel spectrophotometry, revealed LN metastases in mice‐bearing human rectal cancer cells. Occult LN metastases, unrecognized on white‐light imaging and simplified hematoxylin‐eosin analyses, were readily detectable on 5‐ALA‐induced PPIX fluorescence imaging. In vivo macroconfocal images clearly revealed PPIX‐fluorescence‐positive cancer cells in draining lymph vessels and nodes. Together with specific speckled patterns of PPIX‐fluorescence in metastatic lesions, the PPIX‐fluorescence intensity ratio of metastatic and nonmetastatic lesions discriminated metastasis with 100% sensitivity and 100% specificity in excised whole LN samples. These results show that fluorescence diagnosis with 5‐ALA is very accurate in the detection of LN micrometastases of mouse rectal cancer, suggesting that this feasible diagnostic approach is applicable to target sectioning of metastases of resected fresh whole node samples in pathology laboratories. © 2009 UICC

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Fluorescence as a Concept in Colorectal Lymph Node Diagnosis

Cited by 13 publications

References 22 publications

Precise detection of lymph node metastases in mouse rectal cancer by using 5‐aminolevulinic acid

Precise detection of lymph node metastases in mouse rectal cancer by using 5‐aminolevulinic acid

Porphyrin overdrive rewires cancer cell metabolism

Attorney stresses importance of patents in fostering innovation

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