Kerrington Powell

Introduction: Surgical metastasectomy is the removal of metastases from a primary tumor. Despite a high volume of procedures performed annually,¹ a dearth of randomized controlled trial (RCT) evidence is available this procedure. Lack of RCT data has sparked controversy in the literature regarding risk-benefit profiles, particularly for pulmonary metastasectomy in CRC patients.² This point is salient for the resection of pulmonary metastases in CRC, which is the only indication for which a RCT was conducted (PulMiCC; NCT01106261)³; however, this trial failed to accrue, exemplifying only one of the difficulties of producing RCT evidence in this space.⁴ In the absence of randomized evidence, uncontrolled data is currently being used to identify patients who may benefit from surgical intervention.^5,6,7 In this study, we identify potential prognostic biomarkers for CRC patients who may benefit from pulmonary metastasectomy. Methods: Four separate mechanisms of CRC metastasis were investigated. First, researchers compared cell lines that either expressed or did not express SMAD-4 in a mouse model.⁸ As a separate arm, researchers injected a CCR1 antagonist into a SMAD-4 deficient line.⁸ Second, researchers evaluated the expression of the chemokine, CXCL12, in lung metastases through exosome supplementation of mice.⁹ Third, three lines of cells with distinct KRAS mutations (e.g., G12D; G13D; WT) were cultured in seperate lysine/arginine combinations to identify if downstream mutations of KRAS^mut are caused by distinct binding sites for KRAS^wt effectors, hence attracting signaling cascades.¹⁰ Fourth, researchers transfected mice with lentiviral vectors to encode CDX2 overexpression or knockdown cells.¹¹ Results: First, SMAD4 loss led to the expression of the chemokine CCL15, which increased pulmonary metastases through the recruitment of CCR1+ cells.⁸ Mice that expressed SMAD-4 formed significantly fewer lung metastases, with only 13.2% (5/38) of samples forming metastases compared to 38.9% (14/36) in a SMAD-4 deficient cell line.⁸ Second, the expression of the chemokine, CXCL12, was significantly higher in lung metastases of mice that received CT26 exosomes than the control group.⁹ Third, there are signaling discrepancies between the oncogene KRAS point mutations at G12D and G13D with varying prognostic significance for patient outcomes when analyzed retrospectively.¹⁰ Fourth, mice transfected with CDX2-knockdown cells exhibited a higher growth coefficient (i.e., viability) and tumor weight, suggesting CDX2 is associated with a more indolent phenotype.¹¹  Conclusions: Clinically, CCL15 expression is a prognostic marker for more aggressive illness and may be utilized to exclude metastasectomy candidates. CXCL12 may be a driver of CRC lung metastases but warrants further study. Additionally, understanding the underlying processes of these KRAS mutation helps identify mutant subgroups and their clinical relevance. Due to CDX2’s regulatory function, people who express it may be better candidates for metastasectomy. Lastly, even if these biomarkers appear to have prognostic qualities, they must be prospectively validated before they can be used in surgical management.

1. Bartlett EK, Simmons KD, Wachtel H, et al. The rise in metastasectomy across cancer types over the past decade. Cancer. Mar 1 2015;121(5):747-57. doi:10.1002/cncr.29134
2. Gray KD, Molena D. Commentary: To cut is a chance to cure? Lessons to be learned from the PulMiCC trial. J Thorac Cardiovasc Surg. Feb 2022;163(2):493-494. doi:10.1016/j.jtcvs.2021.02.015
3. Milosevic M, Edwards J, Tsang D, et al. Pulmonary Metastasectomy in Colorectal Cancer: updated analysis of 93 randomized patients – control survival is much better than previously assumed. Colorectal Dis. Oct 2020;22(10):1314-1324. doi:10.1111/codi.15113
4. Cook JA. The challenges faced in the design, conduct and analysis of surgical randomised controlled trials. Trials. Feb 6 2009;10:9. doi:10.1186/1745-6215-10-9
5. Lee JH, Gulec SA, Kyshtoobayeva A, Sim MS, Morton DL. Biological factors, tumor growth kinetics, and survival after metastasectomy for pulmonary melanoma. Ann Surg Oncol. Oct 2009;16(10):2834-9. doi:10.1245/s10434-009-0583-5
6. Stein WD, Figg WD, Dahut W, et al. Tumor growth rates derived from data for patients in a clinical trial correlate strongly with patient survival: a novel strategy for evaluation of clinical trial data. Oncologist. Oct 2008;13(10):1046-54. doi:10.1634/theoncologist.2008-0075
7. Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther. Mar 12 2020;5(1):28. doi:10.1038/s41392-020-0134-x
8. Yamamoto T, Kawada K, Itatani Y, et al. Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-Associated Neutrophils through CCL15-CCR1 Axis. Clin Cancer Res. Feb 1 2017;23(3):833-844. doi:10.1158/1078-0432.Ccr-16-0520
9. Wang M, Yang X, Wei M, Wang Z. The Role of CXCL12 Axis in Lung Metastasis of Colorectal Cancer. J Cancer. 2018;9(21):3898-3903. doi:10.7150/jca.26383
10. Tahir R, Renuse S, Udainiya S, et al. Mutation-Specific and Common Phosphotyrosine Signatures of KRAS G12D and G13D Alleles. J Proteome Res. Jan 1 2021;20(1):670-683. doi:10.1021/acs.jproteome.0c00587
11. Yu J, Liu D, Sun X, et al. CDX2 inhibits the proliferation and tumor formation of colon cancer cells by suppressing Wnt/β-catenin signaling via transactivation of GSK-3β and Axin2 expression. Cell Death Dis. Jan 10 2019;10(1):26. doi:10.1038/s41419-018-1263-9