Abstract
.Significance: Many studies in colorectal cancer (CRC) use murine ectopic tumor models to determine response to treatment. However, these models do not replicate the tumor microenvironment of CRC. Physiological information of treatment response derived via diffuse reflectance spectroscopy (DRS) from murine primary CRC tumors provide a better understanding for the development of new drugs and dosing strategies in CRC.Aim: Tumor response to chemotherapy in a primary CRC model was quantified via DRS to extract total hemoglobin content (tHb), oxygen saturation (), oxyhemoglobin, and deoxyhemoglobin in tissue.Approach: A multimodal DRS and imaging probe (0.78 mm outside diameter) was designed and validated to acquire diffuse spectra longitudinally—via endoscopic guidance—in developing colon tumors under 5-fluoruracil (5-FU) maximum-tolerated (MTD) and metronomic regimens. A filtering algorithm was developed to compensate for positional uncertainty in DRS measurementsResults: A maximum increase in was observed in both MTD and metronomic chemotherapy-treated murine primary CRC tumors at week 4 of neoadjuvant chemotherapy, with and fold changes, respectively. No significant changes were observed in tHb.Conclusion: Our study demonstrates the feasibility of DRS to quantify response to treatment in primary CRC models.
Highlights
Our study demonstrates the feasibility of diffuse reflectance spectroscopy (DRS) to quantify response to treatment in primary Colorectal cancer (CRC) models
Primary mouse models of CRC, which more closely replicate primary tumors seen in humans—tumors that develop from dysplastic lesions within the colon epithelium itself—resemble the tumor microenvironment and anatomic location, making them better suited for the study of this disease
This study presents the design, validation, and endoscopic implementation of a smalldiameter [0.78 mm outside diameter (OD)] multimodal optical imaging and DRS probe used in an AOM model of CRC to longitudinally quantify the response in vivo to different neoadjuvant chemotherapy (NAC) (MTD or metronomic)
Summary
Colorectal cancer (CRC) is the fourth leading cause of cancer death in the world, and in the United States, it accounted for 145,600 new cases in 2019.1,2 Preclinical research aimed at understanding the mechanisms of this disease and developing new therapies, frequently focuses on the use of ectopic xenografts or allografts in murine models to study molecular shifts in tumors.[3,4,5] these xenograft/allograft animal models do not properly take into account the Journal of Biomedical OpticsMarch 2020 Vol 25(3)Mundo et al.: Diffuse reflectance spectroscopy to monitor murine colorectal tumor progression. . .influence of the tumor microenvironment[6,7,8] and lack predictive power regarding clinical phase II performance,[9] which limits the inferences from the data obtained from them. Primary mouse models of CRC, which more closely replicate primary tumors seen in humans—tumors that develop from dysplastic lesions within the colon epithelium itself—resemble the tumor microenvironment and anatomic location, making them better suited for the study of this disease These models can be derived via carcinogen administration—such as azoxymethane (AOM)— or in transgenic animals (such as APCmin).[10]. These models can be used to study antitumor drugs and dosing strategies for neoadjuvant chemotherapy (NAC), which is administrated clinically before surgical resection with the aim of shrinking the tumor in patients with locally advanced disease (stage II or III).[11] Typically, the standard NAC regimen is based on the maximum-tolerated dose (MTD) approach,[8] which requires the cycling of treatment due to its associated toxicity and side effects (nausea, fever, pain). The concept of low-dose continuous (metronomic) chemotherapy has been developed over the past 15 years, as it minimizes treatment side effects while targeting the endothelial cells of the tumor vasculature, which are not allowed to recover.[12,13] This therapy has been explored as NAC in clinical studies of ovarian, cervical, and breast cancers, where tumor reduction was observed.[14,15,16] Novel administration strategies for CRC—with the intent of understanding the mechanistic effects of this approach, as well as to identify potential clinically viable (endoscopic) biomarkers of positive therapy response—require the use of in vivo, primary models of the disease
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