Metastasis Organotropism: Redefining the Congenial Soil

Abstract

Metastasis is the most devastating stage of cancer progression and causes the majority of cancer-related deaths. Clinical observations suggest that most cancers metastasize to specific organs, a process known as ''organotropism.'' Elucidating the underlying mechanisms may help identify targets and treatment strategies to benefit patients. This review summarizes recent findings on tumor-intrinsic properties and their interaction with unique features of host organs, which together determine organ-specific metastatic behaviors. Emerging insights related to the roles of metabolic changes, the immune landscapes of target organs, and variation in epithelial-mesenchymal transitions open avenues for future studies of metastasis organotropism. Mechanisms Underlying Organ-Tropism of Metastasis Classic ''Seed and Soil'' MechanismsStephen Paget stipulated that both cancer cell-intrinsic properties (''seed'') and the congenial ME (''soil'') are essential for metastasis formation (Paget, 1889). Research in the past few decades has greatly enhanced our understanding of the molecular and cellular nature of both ''seed'' and ''soil''. In this section, we will review some mechanisms of organ-specific metastasis focusing on the organ-specific ME. Bone TropismCancers disseminate to bone with different frequencies (Table 1). Breast and prostate cancers are the principal cancers that metastasize to bone (Budczies et al., 2015; DiSibio and French, 2008). Bone and bone marrow comprise unique cell types including osteoblasts, osteocytes, and osteoclasts. Osteoclasts

Risk factors of distant metastasis after surgery among different breast cancer subtypes: a hospital-based study in Indonesia

“…Therefore, identification of determinants associated with an elevated risk of distant metastasis according to breast cancer subtypes as well as some potential interventions to lower the risk has emerged as an important study field in oncology. Distant metastasis involves a complex interaction of primary tumor milieu and systemic factors including cancer cell proliferation, differentiation, angiogenesis, and the microenvironment [34]. Several clinicopathological factors affect specific clinical outcomes of breast cancer management.…”

“…The most common sites for distant metastasis from breast cancer are the bone (65%), followed by the liver, lung, and brain [56]. Distant spread to certain organs is an orderly process known as metastatic organotropism and is regulated by a number of factors including intrinsic breast cancer subtypes, metabolic changes, molecular alterations of the cancer cells, host immune responses, and tumor microenvironment [34,57]. Coordinated activation of several pathways including Notch, Wnt/ß-catenin, and Hedgehog, as well as proteins including COX2, metalloproteinases, and vascular endothelial growth factor (VEGF) collectively facilitate the release of cancer cells and the infiltration into distant organs [53].…”

“…Chemokines, interleukin, HIF, and Wnt signaling are activated in Her2enriched and luminal breast cancer subtypes to mediate liver metastasis [57]. In addition, growth factors, tumor growth factor-beta (TGFβ), and COX2 are responsible for lung metastasis in non-luminal breast cancer subtypes [34]. Future studies to understand more details of the association of molecular subtypes and organ-specific metastasis will improve the future clinical management, mode of surveillance, and new targeted treatment for breast cancer patients.…”

Ral GTPases promote metastasis by controlling biogenesis and organ colonization of exosomes

“…Independently of the precise mode of action of PA, further work is required to determine how the Ral-PLD1-PA axis is connected to other known machineries of ILV biogenesis. Priming of metastatic niches by (soluble or) EV-mediated factors takes central stages in cancer progression (Gao et al, 2019;Peinado et al, 2017) and identification of molecular machineries that underlie this condition could point to new therapeutic or diagnostic targets. Our study demonstrates that Ral GTPases enhance the formation of lung metastasis by promoting the secretion of exosomes within primary tumors.…”

Machine learning of genomic features in organotropic metastases stratifies progression risk of primary tumors

“…Collectively, given that 15 out of the 16 cancer types (9,849 out of 10,038 samples) exhibit signi cant correlation of metastatic site distributions between MSK and FMI cohorts (PCC > 0.5, p < 0.05, Supplementary Fig. 4a), we concluded from a big-data perspective that dissemination direction in majority of metastatic cancers is strongly organotropic in a statistically robust manner, which implies that organotropic metastasis is highly nonrandom and in part driven by certain potential factors including tissue of origin, vascular pattern, genetic background and congenial microenvironment 15,33,34 .…”