Abstract
Second-harmonic generation (SHG) allows for the analysis of tumor collagen structural changes throughout metastatic progression. SHG directionality, measured through the ratio of the forward-propagating to backward-propagating signal (F/B ratio), is affected by collagen fibril diameter, spacing, and disorder of fibril packing within a fiber. As tumors progress, these parameters evolve, producing concurrent changes in F/B. It has been recently shown that the F/B of highly metastatic invasive ductal carcinoma (IDC) breast tumors is significantly different from less metastatic tumors. This suggests a possible relationship between the microstructure of collagen, as measured by the F/B, and the ability of tumor cells to locomote through that collagen. Utilizing in vitro collagen gels of different F/B ratios, we explored the relationship between collagen microstructure and motility of tumor cells in a “clean” environment, free of the myriad cells, and signals found in in vivo. We found a significant relationship between F/B and the total distance traveled by the tumor cell, as well as both the average and maximum velocities of the cells. Consequently, one possible mechanism underlying the observed relationship between tumor F/B and metastatic output in IDC patient samples is a direct influence of collagen structure on tumor cell motility.
Highlights
Breast cancer is the most frequently diagnosed form of invasive carcinoma and the second leading cause of cancer-induced mortality in the female population.1 90% of cancer mortalities are the result of metastasis of the tumor to a secondary location.[2]
It has previously been shown that the average F/B ratio of the primary tumor of patients with invasive ductal carcinoma (IDC) varies with the extent of lymph node involvement upon clinical presentation.[10]
The fact that tumor cells themselves can affect F/B, and that alteration of enzymes present in the stroma can alter F/B, suggests that both tumor and stromal cells play key roles in defining the matrix microstructure that dictates F/B. These results suggest that the relationship between F/B and metastatic output observed in patient IDC samples can be explained at least in part by a direct influence of collagen microstructure on tumor cell motility
Summary
Breast cancer is the most frequently diagnosed form of invasive carcinoma and the second leading cause of cancer-induced mortality in the female population.1 90% of cancer mortalities are the result of metastasis of the tumor to a secondary location.[2] The tumor stroma, consisting of nontumor cells and the extracellular matrix (ECM), has been known to play a vital role in metastatic efficiency.[3] Collagen, a key component of the ECM, produces an intrinsic optical signal caused by the scattering phenomenon second-harmonic generation (SHG), which allows us to monitor changes in the tumor ECM throughout tumor progression. SHG occurs when two incoming photons scatter off of a noncentrosymmetric structure to produce one emission photon at twice the energy and half the wavelength of the individual incoming photons. SHG emission is coherent, the directionality of the signal, often quantified through the ratio of the forward-propagating to backward-propagating signal (the F/B ratio), is affected by the properties of a collagen fiber such as fibril diameter, spacing, and order versus disorder in fibril packing within a fiber.[4,5,6] Collectively, we will describe these properties as the collagen fiber “microstructure.”[7] Multiphoton imaging of fluorescence and SHG signals has shown that tumor cells move more efficiently along
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