Second-harmonic generation imaging of cancer

Keikhosravi, Adib; Bredfeldt, Jeremy S.; Sagar, Abdul Kader; Eliceiri, Kevin W.

doi:10.1016/b978-0-12-420138-5.00028-8

Cited by 79 publications

(62 citation statements)

References 67 publications

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“…These fiber features were chosen because they appear to be altered in many cancer types compared with normal tissue counterparts. 19 Fiber length and width are calculated as pixel values. Alignment represents the overall directionality of fibers within the image on a scale from 0-1, where 1 indicates all fibers are orientated at the same angle.…”

Section: Computational Collagen Fiber Segmentation and Quantificationmentioning

confidence: 99%

“…Using second harmonic generation imaging, a number of groups have shown that changes in collagen fiber structure and organization during tumor initiation and progression have biological consequences and correlate with clinical outcomes in a number of other solid tumor types. [19][20][21] Although increased stromal collagen content has long been clinically documented in pancreatic ductal adenocarcinoma cases, its specific topology in relationship to the malignant glands has yet to be investigated in human tissue specimens. In this study, we utilized second harmonic generation imaging to interrogate and quantify collagen changes in relation to histologic features within pancreatic carcinomas.…”

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confidence: 99%

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Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

et al. 2015

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Pancreatic ductal adenocarcinoma continues to be one of the most difficult diseases to manage with one of the highest cancer mortality rates. This is due to several factors including nonspecific symptomatology and subsequent diagnosis at an advanced stage, aggressive metastatic behavior that is incompletely understood, and limited response to current therapeutic regimens. As in other cancers, there is great interest in studying the role of the tumor microenvironment in pancreatic ductal adenocarcinoma and whether components of this environment could serve as research and therapeutic targets. In particular, attention has turned toward the desmoplastic collagen-rich pancreatic ductal adenocarcinoma stroma for both biological and clinical insight. In this study, we used quantitative second harmonic generation microscopy to investigate stromal collagen organization and structure in human pancreatic ductal adenocarcinoma pathology tissues compared with non-neoplastic tissues. Collagen topology was characterized in whole-tissue microarray cores and at specific pathology-annotated epithelial-stroma interfaces representing 241 and 117 patients, respectively. We quantitatively demonstrate that a unique collagen topology exists in the periductal pancreatic ductal adenocarcinoma stroma. Specifically, collagen around malignant ducts shows increased alignment, length, and width compared with normal ducts and benign ducts in a chronic pancreatitis background. These findings indicate that second harmonic generation imaging can provide quantitative information about fibrosis that complements traditional histopathologic insights and can serve as a rich field for investigation into pathogenic and clinical implications of reorganized collagen as a pancreatic ductal adenocarcinoma disease marker. Pancreatic ductal adenocarcinoma is one of the most devastating human malignancies. It is currently the fourth leading cause of cancer death and projects to become the second leading cause by 2030. 1 The 5-year relative survival rate has remained in the single digits for decades. Pancreatic ductal adenocarcinoma is notoriously difficult to detect before an advanced, inoperable stage is reached due to nonspecific symptomatology and the retroperitoneal location of the pancreas, which makes palpation or routine biopsy of suspicious masses difficult. Recent advances in the sensitivity and specificity of preoperative imaging modalities such as computer tomography, magnetic resonance imaging, positron emission tomography, endoscopic ultrasonography, and endoscopic retrograde cholangiopancreatography have played an important role in enhancing pancreatic ductal adenocarcinoma diagnosis, detailing the relationship of lesions to nearby anatomical structures, and determining the course of management. 2 Despite these advances, only 10-15% of patients are diagnosed at a localized disease stage when surgical resection is possible as a potential curative therapy. However, postsurgical recurrence rates are high with 5-year survival rate of

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Section: Computational Collagen Fiber Segmentation and Quantificationmentioning

confidence: 99%

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confidence: 99%

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

et al. 2015

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“…Interstitial fibrillar collagens have a characteristic triple helical structure, composed of three polypeptide alpha chains, which confers high tensile strength and an ideal structural support scaffold for tissue integrity. By exploiting the ability to detect and visualize fibrillar collagens with a number of techniques including Second Harmonic Generation (SHG) imaging [44–49], it is now appreciated that the normal architectural integrity of fibrillar collagen networks is lost during cancer progression. This has been shown to result in a number of biological consequences, such as tissue stiffening and the transmission of mechanical signaling [50–52], altered metabolic profiles [53], immune cell exclusion from the primary tumor [54], and permissive landscapes for cell invasion [41,55].…”

Section: Introductionmentioning

confidence: 99%

Highly aligned stromal collagen is a negative prognostic factor following pancreatic ductal adenocarcinoma resection

et al. 2016

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Risk factors for pancreatic ductal adenocarcinoma (PDAC) progression after surgery are unclear, and additional prognostic factors are needed to inform treatment regimens and therapeutic targets. PDAC is characterized by advanced sclerosis of the extracellular matrix, and interactions between cancer cells, fibrillar collagen, and other stromal components play an integral role in progression. Changes in stromal collagen alignment have been shown to modulate cancer cell behavior and have important clinical value in other cancer types, but little is known about its role in PDAC and prognostic value. We hypothesized that the alignment of collagen is associated with PDAC patient survival. To address this, pathology-confirmed tissues from 114 PDAC patients that underwent curative-intent surgery were retrospectively imaged with Second Harmonic Generation (SHG) microscopy, quantified with fiber segmentation algorithms, and correlated to patient survival. The same tissue regions were analyzed for epithelial-to-mesenchymal (EMT), α-SMA, and syndecan-1 using complimentary immunohistostaining and visualization techniques. Significant inter-tumoral variation in collagen alignment was found, and notably high collagen alignment was observed in 12% of the patient cohort. Stratification of patients according to collagen alignment revealed that high alignment is an independent negative factor following PDAC resection (p = 0.0153, multivariate). We also found that epithelial expression of EMT and the stromal expression of α-SMA and syndecan-1 were positively correlated with collagen alignment. In summary, stromal collagen alignment may provide additional, clinically-relevant information about PDAC tumors and underscores the importance of stroma-cancer interactions.

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“…The analysis showed that the cells aligned perpendicularly to the spheroid surface due to applied traction forces from the cells in the spheroid to reorganize the collagen matrix (23). Although the density and alignment of fibrillary collagen are clearly important markers in diagnosing a human breast carcinoma's stage (12,14), biopsies merely provide static "snapshots" of the morphology …”

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confidence: 99%

“…Fig. 1 presents hematoxylin/eosin (H&E)-stained biopsy slices of breast cancer imaged by second harmonic generation (SHG) under a two-photon confocal microscopy (A1R MP; Nikon) (detailed information provided in SI Appendix, SI Text) (6,14,15). Fig.…”

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confidence: 99%

Oriented collagen fibers direct tumor cell intravasation

Han

Chen

Yuan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

296

248

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In this work, we constructed a Collagen I-Matrigel composite extracellular matrix (ECM). The composite ECM was used to determine the influence of the local collagen fiber orientation on the collective intravasation ability of tumor cells. We found that the local fiber alignment enhanced cell-ECM interactions. Specifically, metastatic MDA-MB-231 breast cancer cells followed the local fiber alignment direction during the intravasation into rigid Matrigel (∼10 mg/mL protein concentration).M etastasis is a lethal milestone in cancer: Cells escape from the confinement of primary tumor sites (intravasation), invade tissues as well as the lymphatic and vascular systems, and finally colonize (extravasation) distant sites. It has been estimated that less than 1% of tumor cells undergo this process, but metastasis contributes to more than 90% of cancerrelated deaths (1, 2). Metastasis involves both genetic and epigenetic alternation of tumor cells, as well as external biochemical and biophysical microenvironments (3-5). Pathology studies suggest that metastatic tumor cells exhibit highly branched morphologies and distinct aligned registration with aligned extracellular matrix (ECM) during metastatic tumor progression (4, 5).We address three important questions concerning metastasis. (i) Can we build in vitro complex ECM structures with heterogeneously oriented collagen fibers and basement membrane components to mimic the cancer cell intravasation process? (ii) How does aligned collagen influence cell intravasation into/ through the basement membrane before entering vessels? (iii) After cell detachment from the primary tumor site, how does a heterogeneous ECM with a varying degree of local fiber alignment influence cell intravasation and subsequent penetration into the basement membrane during their intravasation process? The major obstacle to addressing these questions is the difficulty in constructing both an in vitro 3D microenvironment to mimic the above process and flexible controls of the environmental parameters, such as fiber orientations in a complex collagen/Matrigel composite, nutrition, oxygen, drug concentrations, etc.In breast cancer metastasis, cancer cells are believed to reorganize and progress through the interstitial ECM matrix, break through the basement membrane, and enter blood vessels or lymphatic capillaries (6-10). Fig. 1C presents a schematic illustration of the intravasation process in metastasis. Tumor-associated collagen signatures (TACS), basically environmentally elevated collagen density and collagen fiber reorganization, are used to stage mammary carcinoma tumor progression levels (6, 11-13). Fig. 1 presents hematoxylin/eosin (H&E)-stained biopsy slices of breast cancer imaged by second harmonic generation (SHG) under a two-photon confocal microscopy (A1R MP; Nikon) (detailed information provided in SI Appendix, SI Text) (6, 14, 15). Fig. 1 A, 1-3 shows the stained human invasive ductal carcinoma tumor at grade I. In the enlarged figures (Fig. 1 A, 2 and 3), the cells have well-defined bord...

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Second-harmonic generation imaging of cancer

Cited by 79 publications

References 67 publications

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

Highly aligned stromal collagen is a negative prognostic factor following pancreatic ductal adenocarcinoma resection

Oriented collagen fibers direct tumor cell intravasation

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