Biphasic α2β1 Integrin Expression in Breast Cancer Metastasis to Bone

Abstract

Integrins participate in the pathogenesis and progression of tumors at many stages during the metastatic cascade. However, current evidence for the role of integrins in breast cancer progression is contradictory and seems to be dependent on tumor stage, differentiation status, and microenvironmental influences. While some studies suggest that loss of α2β1 enhances cancer metastasis, other studies suggest that this integrin is pro-tumorigenic. However, few studies have looked at α2β1 in the context of bone metastasis. In this study, we aimed to understand the role of α2β1 integrin in breast cancer metastasis to bone. To address this, we utilized in vivo models of breast cancer metastasis to bone using MDA-MB-231 cells transfected with an α2 expression plasmid (MDA-OEα2). MDA cells overexpressing the α2 integrin subunit had increased primary tumor growth and dissemination to bone but had no change in tumor establishment and bone destruction. Further in vitro analysis revealed that tumors in the bone have decreased α2β1 expression and increased osteolytic signaling compared to primary tumors. Taken together, these data suggest an inverse correlation between α2β1 expression and bone-metastatic potential. Inhibiting α2β1 expression may be beneficial to limit the expansion of primary tumors but could be harmful once tumors have established in bone.

Small Extracellular Vesicles from Hypoxic Triple-Negative Breast Cancer Cells induce Oxygen-dependent Cell Invasion

“…Integrin profiling in cancer cells differ based on tumor aggressiveness, cellular origin and tumoral progression [49], and this profile can be passed onto extracellular vesicles [50], thus aiding vesicular trafficking [51], organotropism [10] and metastasis [52]. β1 and β3 integrin subunits are often upregulated in cancer and linked to responses of cell motility [53], adhesion [54], invasion [55,56] and angiogenesis [57,58]; hence, we investigated whether they are affected by SEVh exposure. We found that a hypoxic atmosphere, instead of the signaling from SEVh, modulates gene and protein expression of β1 and β3 integrins; however, the availability of these integrins to the cell surface in hypoxia differs in the presence of SEVh.…”

Targeting Integrins for Cancer Therapy - Disappointments and Opportunities

“…Integrin expression has been observed to differ between primary and metastatic lesions indicating that therapies may affect one but not the other stage. e.g., expression of integrin α2β1 was shown to promote tumor growth of a breast cancer cell line whereas α2β1 expression was attenuated once the breast cancer cells colonized the bone ( Moritz et al, 2021 ). In fact, integrins have been shown in some cases to have opposing roles at different stages and repress rather than support disease progression and metastasis.…”

“…Deletion of β1 integrins also increased prostate cancer progression in a genetic mouse model ( Moran-Jones et al, 2012 ). Likewise, specific deletion of one of the β1 integrins, α2β1, was demonstrated to inhibit tumor metastasis in mouse models for breast or prostate cancer ( Ramirez et al, 2011 ; Moritz et al, 2021 ). Although similar examples are not described for the αv integrins targeted in clinical trials thus far, these findings suggest that therapeutic targeting of integrins may lead to complex responses in patients that may vary for individual patients.…”

“…Studies using genetically engineered mouse models or using human tumor cells transplanted in immune deficient mice have extensively shown that deletion of integrins in cancer cells or preventing integrin function with blocking antibodies or peptides could interfere with tumor growth, metastasis, and resistance to chemo- or radiotherapy ( Juliano and Varner, 1993 ; Danen, 2005 ; Desgrosellier and Cheresh, 2010 ; Hamidi and Ivaska, 2018 ; Cooper and Giancotti, 2019 ). For the large family of β1 integrins, dual roles have been identified in growth versus metastasis, indicating that caution is warranted for their application as therapeutic targets ( Ramirez et al, 2011 ; Moran-Jones et al, 2012 ; Truong et al, 2014 ; Moritz et al, 2021 ). Integrins such as αvβ3, αvβ5, and α5β1, are not only expressed on tumor cells but are also induced on endothelial cells during the process of angiogenesis ( Friedlander et al, 1995 ; Avraamides et al, 2008 ).…”

Integrin β1 in Pancreatic Cancer: Expressions, Functions, and Clinical Implications

“…For example, while depletion of integrin β1 suppresses the progression of several tumors, it could enhance tumorigenesis and proliferation in prostate cancer [ 196 ]. Likewise, Moritz et al present a dual role of integrin α2β1 in breast cancer, that inhibiting α2β1 expression may be beneficial to limit the expansion of primary tumors but could be harmful once tumors establish in bone [ 199 ]. Besides, it has been reported that some antagonists can, to some extent, be agonists under certain conditions and induce the receptor to extend and adapt to a high-affinity ligand-binding state, which may paradoxically enhance angiogenesis and tumor growth [ 200 , 201 , 202 ].…”