The therapeutic targeting of extracellular proteins is becoming hugely attractive in light of evidence implicating the tumour microenvironment as pivotal in all aspects of tumour initiation and ...progression. Members of the lysyl oxidase (LOX) family of proteins are secreted by tumours and are the subject of much effort to understand their roles in cancer. In this Review we discuss the roles of members of this family in the remodelling of the tumour microenvironment and their paradoxical roles in tumorigenesis and metastasis. We also discuss how targeting this family of proteins might lead to a new avenue of cancer therapeutics.
Radiotherapy plays a central part in curing cancer. For decades, most research on improving treatment outcomes has focused on modulating radiation-induced biological effects on cancer cells. ...Recently, we have better understood that components within the tumour microenvironment have pivotal roles in determining treatment outcomes. In this Review, we describe vascular, stromal and immunological changes that are induced in the tumour microenvironment by irradiation and discuss how these changes may promote radioresistance and tumour recurrence. We also highlight how this knowledge is guiding the development of new treatment paradigms in which biologically targeted agents will be combined with radiotherapy.
Tumor metastasis is a highly complex, dynamic, and inefficient process involving multiple steps, yet it accounts for more than 90% of cancer-related deaths. Although it has long been known that ...fibrotic signals enhance tumor progression and metastasis, the underlying molecular mechanisms are still unclear. Identifying events involved in creating environments that promote metastatic colonization and growth are critical for the development of effective cancer therapies. Here, we show a critical role for lysyl oxidase (LOX) in establishing a milieu within fibrosing tissues that is favorable to growth of metastastic tumor cells. We show that LOX-dependent collagen crosslinking is involved in creating a growth-permissive fibrotic microenvironment capable of supporting metastatic growth by enhancing tumor cell persistence and survival. We show that therapeutic targeting of LOX abrogates not only the extent to which fibrosis manifests, but also prevents fibrosis-enhanced metastatic colonization. Finally, we show that the LOX-mediated collagen crosslinking directly increases tumor cell proliferation, enhancing metastatic colonization and growth manifesting in vivo as increased metastasis. This is the first time that crosslinking of collagen I has been shown to enhance metastatic growth. These findings provide an important link between ECM homeostasis, fibrosis, and cancer with important clinical implications for both the treatment of fibrotic disease and cancer.
More than 90% of cancer patient mortality is attributed to metastasis. In this study, we investigated a role for the lysyl oxidase-related enzyme lysyl oxidase-like 2 (LOXL2) in breast cancer ...metastasis, in both patient samples and in vivo models. Analysis of a published microarray data set revealed that LOXL2 expression is correlated with metastasis and decreased survival in patients with aggressive breast cancer. In immunocompetent or immunocompromised orthotopic and transgenic breast cancer models we showed that genetic, chemical or antibody-mediated inhibition of LOXL2 resulted in decreased metastasis. Mechanistic investigations revealed that LOXL2 promotes invasion by regulating the expression and activity of the extracellular proteins tissue inhibitor of metalloproteinase-1 (TIMP1) and matrix metalloproteinase-9 (MMP9). We found that LOXL2, TIMP1, and MMP9 are coexpressed during mammary gland involution, suggesting they function together in glandular remodeling after weaning. Finally, we found that LOXL2 is highly expressed in the basal/myoepithelial mammary cell lineage, like many other genes that are upregulated in basal-like breast cancers. Our findings highlight the importance of LOXL2 in breast cancer progression and support the development of anti-LOXL2 therapeutics for the treatment of metastatic breast cancer.
Cancer-associated fibroblasts enhance cancer progression when activated by tumor cells through mechanisms not yet fully understood. Blocking mammary tumor cell-derived lysyl oxidase-like 2 (LOXL2) ...significantly inhibited mammary tumor cell invasion and metastasis in transgenic and orthotopic mouse models. Here, we discovered that tumor-derived LOXL2 directly activated stromal fibroblasts in the tumor microenvironment. Genetic manipulation or antibody inhibition of LOXL2 in orthotopically grown mammary tumors reduced the expression of α-smooth muscle actin (α-SMA). Using a marker for reticular fibroblasts, it was determined that expression of α-SMA was localized to fibroblasts recruited from the host tissue. This marker also revealed that the matrix present in tumors with reduced levels of LOXL2 was more scattered compared with control tumors which exhibited matrices with dense, parallel alignments. Importantly, in vitro assays revealed that tumor-derived LOXL2 and a recombinant LOXL2 protein induced fibroblast branching on collagen matrices, as well as increased fibroblast-mediated collagen contraction and invasion of fibroblasts through extracellular matrix. Moreover, LOXL2 induced the expression of α-SMA in fibroblasts grown on collagen matrices. Mechanistically, it was determined that LOXL2 activated fibroblasts through integrin-mediated focal adhesion kinase activation. These results indicate that inhibition of LOXL2 in tumors not only reduces tumor cell invasion but also attenuates the activation of host cells in the tumor microenvironment.
These findings reveal new insight into the mechanisms of fibroblast activation, a novel function of LOXL2, and further highlight the importance of generating LOXL2-targeted therapies for the prevention of tumor progression and metastasis.
Gynaecological carcinosarcomas are the most lethal gynaecological malignancies that are often highly resistant to standard chemotherapy. They are composed of both carcinomatous and sarcomatous ...components and are associated with high rates of metastatic disease. Due to their rarity, molecular studies have been carried out on relatively few tumours, revealing a broad spectrum of heterogeneity. In this review, we have collated the gene mutations, gene expression, epigenetic regulation and protein expression reported by a number of studies on gynaecological carcinosarcomas. Based on these results, we describe potential therapeutics that may demonstrate efficacy and present any pre-clinical studies that have been carried out. We also describe the pre-clinical models currently available for future research to assess the potential of molecularly matched therapies. Interestingly, over-expression of many biomarkers in carcinosarcoma tumours often doesn’t correlate with a worse prognosis. Therefore, we propose that profiling the mutational landscape, gene expression, and gene amplification/deletion may better indicate potential treatment strategies and predict response, thus improving outcomes for women with this rare, aggressive disease.
Billions of people around the globe are well-acquainted with SpongeBob Square-pants and the antics of the title character and his friends on Bikini Bottom. By the same token, there is an absence of ...public discourse about the whitewashing of violent American military activities through SpongeBob’s occupation and reclaiming of the bottom of Bikini Atoll’s lagoon. SpongeBob Squarepants and his friends play a role in normalizing the settler colonial takings of Indigenous lands while erasing the ancestral Bikinian people from their nonfictional homeland. This article exposes the complicity of popular culture in maintaining American military hegemonies in Oceania while amplifying the enduring indigeneity (Kauanui 2016) of the Marshallese people, who maintain deeply spiritual and historical connections to land—even land they cannot occupy due to residual radiation contamination from US nuclear weapons testing—through a range of cultural practices, including language, song, and weaving. This article also considers the gendered violence of nuclear colonialism and the resilience of Marshallese women.
The University of Washington (UW) continues to create opportunities to engage all students in transformational undergraduate educational opportunities, such as study abroad.
This article describes ...specific efforts to increase inclusion for student-athletes in study abroad, particularly for first-generation students, including low-income students of color. Given the overrepresentation of students of color in sports vis-à-vis the larger student body at predominantly white institutions (PWIs), like UW, service-learning in communities beyond campus boundaries provides opportunities to apply international learning to a local context and to create a continuum of learning.
By coupling educational theories from the classroom—particularly theories related to power and privilege—with community-based leadership in local communities, students are better prepared to actively engage in improving their own institutions. During the summers of 2013, 2014, and 2015, the author was the instructor for study abroad courses to French Polynesia with student-athletes. The courses were for 12 days (10 days on the ground and 2 days of flying), the maximum time that football players could be away from required summer workouts. This paper examines student evaluations from the French Polynesia trip in 2015.
Student-athlete evaluations of a study abroad experience underscored: the transformative impact of study abroad to their academic, social, and athletic lives; the benefit of creating family-like relationships outside the confines of their sport; an appreciation for the many forms where indigenous knowledge resides, such as in navigation, dance, fishing, weaving, and cooking; intense feelings of culture shock upon return to the US, even when the trip is short in duration; a desire to engage with the diverse communities in Seattle beyond the scope of the program's structure, and; frustration, particularly for the male student-athletes, about the ways coaches, family, and friends wanted to frame the study abroad experience as a tourist experience in the South Pacific. In this regard, the student-athletes encountered stereotypes from their own communities that framed Oceania as a place for tourism, and student-athletes as uninterested in deep engagement with research and theory–stereotypes that the student-athletes resist.
This paper explains how the findings, coupled with Hartman and Kiely’s theories for global service learning (GSL), lead to recommendations for strengthening the future connections between global and local learning for students.
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