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High-grade serous ovarian cancer is the most common and lethal gynecologic malignancy, which is often attributed to the lack of available screenings, allowing the disease to progress unnoticed until it is diagnosed at more aggressive stages. As such, identifying signals in the tumor microenvironment involved in the primary metastasis of tumorigenic fallopian tube epithelial (FTE) cells to the ovary could provide new avenues for prevention, diagnostics, or therapeutic intervention. Since our previous work identified that the interaction of tumorigenic FTE and the ovary causes the release of norepinephrine (NE) from the ovary, we intended to determine the effects of ovarian NE on signaling and invasion of tumorigenic FTE models and high-grade serous ovarian cancer cell lines. We demonstrate that NE does not universally enhance migration, invasion, or adhesion by using multiple cell types but does alter specific oncogenic protein expression in certain models. In vivo, we found that blocking NE signaling via slow-release propranolol pellets significantly increased survival time in mice injected intraperitoneally with murine FTE cells engineered to stably express shRNA for PTEN and an activated KRAS expression construct. Finally, we identified that the metabolome released from the ovary is variable depending upon which cell type it is cocultured with, suggesting that distinct driver mutations in fallopian tube epithelial tumor models and early lesions can alter specific metabolomes within the surrounding ovarian microenvironment. These metabolomes provide the next frontier for evaluating local signals of the tumor microenvironment that facilitate ovarian spread of FTE lesions.
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Progesterone functions as a steroid hormone involved in female reproductive physiology. While some reproductive disorders manifest with symptoms that can be treated by progesterone or synthetic progestins, recent data suggest that women also seek botanical supplements to alleviate these symptoms. However, botanical supplements are not regulated by the U.S. Food and Drug Administration and therefore it is important to characterize and quantify the inherent active compounds and biological targets of supplements within cellular and animal systems. In this study, we analyzed the effect of two natural products, the flavonoids, apigenin and kaempferol, to determine their relationship to progesterone treatment in vivo. According to immunohistochemical analysis of uterine tissue, kaempferol and apigenin have some progestogenic activity, but do not act in exactly the same manner as progesterone. More specifically, kaempferol treatment did not induce HAND2, did not change proliferation, and induced ZBTB16 expression. Additionally, while apigenin treatment did not appear to dramatically affect transcripts, kaempferol treatment altered some transcripts (44%) in a similar manner to progesterone treatment but had some unique effects as well. Kaempferol regulated primarily unfolded protein response, androgen response, and interferon-related transcripts in a similar manner to progesterone. However, the effects of progesterone were more significant in regulating thousands of transcripts making kaempferol a selective modifier of signaling in the mouse uterus. In summary, the phytoprogestins, apigenin and kaempferol, have progestogenic activity in vivo but also act uniquely.
Assuntos
Quempferóis , Progesterona , Camundongos , Animais , Feminino , Progesterona/farmacologia , Quempferóis/farmacologia , Apigenina/farmacologia , Progestinas/farmacologia , ÚteroRESUMO
High grade serous ovarian cancer (HGSOC), the most lethal histotype of ovarian cancer, frequently arises from fallopian tube epithelial cells (FTE). Once transformed, tumorigenic FTE often migrate specifically to the ovary, completing the crucial primary metastatic step and allowing the formation of the ovarian tumors after which HGSOC was originally named. As only the fimbriated distal ends of the fallopian tube that reside in close proximity to the ovary develop precursor lesions such as serous tubal intraepithelial carcinomas, this suggests that the process of transformation and primary metastasis to the ovary is impacted by the local microenvironment. We hypothesize that chemical cues, including small molecules and proteins, may help stimulate the migration of tumorigenic FTE to the ovary. However, the specific mediators of this process are still poorly understood, despite a recent growth in interest in the tumor microenvironment. Our previous work utilized imaging mass spectrometry (IMS) to identify the release of norepinephrine (NE) from the ovary in co-cultures of tumorigenic FTE cells with an ovarian explant. We predicted that tumorigenic FTE cells secreted a biomolecule, not produced or produced with low expression by non-tumorigenic cells, that stimulated the ovary to release NE. As such, we utilized an IMS mass-guided bioassay, using NE release as our biological marker, and bottom-up proteomics to demonstrate that a secreted protein, SPARC, is a factor produced by tumorigenic FTE responsible for enhancing release of ovarian NE and influencing primary metastasis of HGSOC. This discovery highlights the bidirectional interplay between different types of biomolecules in the fallopian tube and ovarian microenvironment and their combined roles in primary metastasis and disease progression.
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Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer-related death in women. Although outcomes have improved in recent years, there remains an unmet clinical need to understand the early pathogenesis of ovarian cancer in order to identify new diagnostic approaches and agents of chemoprevention and chemotherapy. While high grade serous ovarian cancer (HGSOC), the most abundant histotype, was initially thought to arise from the ovarian surface epithelium, there is an increasing body of evidence suggesting that HGSOC originates in the fallopian tube. With this new understanding of cell of origin, understanding of disease development requires analysis with a novel perspective. Currently, factors that drive the initiation and migration of dysplastic tubal epithelial cells from the fallopian tube to the ovary are not yet fully defined. These factors include common mutations to fallopian tube epithelial cells, as well as factors originating from both the fallopian tube and ovary which are capable of inducing transformation and dissemination in said cells. Here, we review these changes, their causative agents, and various potential means of intervention.
Assuntos
Cistadenocarcinoma Seroso/secundário , Neoplasias das Tubas Uterinas/patologia , Tubas Uterinas/patologia , Neoplasias Ovarianas/patologia , Cistadenocarcinoma Seroso/terapia , Neoplasias das Tubas Uterinas/terapia , Feminino , Humanos , Neoplasias Ovarianas/terapia , PrognósticoRESUMO
Neutropenic enterocolitis (NE) is a life-threatening infection of the immunocompromised. NE ubiquitously affects the cecum, often with involvement of the ascending colon and ileum. Classically, NE is associated with high mortality leading to the frequent use of aggressive treatment strategies including surgery. Although conservative approaches are often successful, there are currently no standardized treatment guidelines for NE and it is unclear when such strategies should be implemented. Here, we describe a patient with suspected chemotherapy-associated NE despite having previously undergone a right hemicolectomy. As computed tomography imaging failed to provide a conclusive diagnosis, we performed a gentle endoscopic evaluation that affirmed a diagnosis of NE of the transverse colon, and suggested the patient would benefit from conservative treatment. This case demonstrates that endoscopy can be a safe and useful tool in the diagnosis of NE, and is an important reminder that NE can affect any part of the gastrointestinal tract.
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While the metastatic spread of breast cancer is well documented, the breast is seldom a site for metastasis. Non-mammillary cancers can involve the breast or axilla, though this is exceedingly rare with few reported instances. Here, we present the case of a 62-year-old woman who attended an outpatient breast clinic with a history of an ileal carcinoid tumor complicated by multi-organ metastasis. Her disease was in clinical remission for several years, though she recently re-presented with a single solitary lesion to the breast that was later confirmed as a recurrence of her carcinoid tumor. This serves as an important reminder that the breast can indeed be a site for metastasis. As metastatic breast lesions can often be difficult to diagnose, it is essential to obtain a thorough medical history in order to determine the appropriate clinical course.
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High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube and then spread to the ovary. Our objective was to evaluate the role of multicellular tumor spheroids (MTS) in ovarian metastasis. By testing a panel of murine oviductal epithelial (MOE) cells with genetic alterations mimicking those seen in HGSOC, we found that loss of PTEN allowed MTS formation under ultra-low adhesion conditions. Confirming these results in vivo, MTS-like structures were observed in the oviducts of PAX8Cre/+ PTENflox/flox mice. MOE PTENshRNA cells could incorporate up to 25% wild type cells into MTS, while higher percentages of wild type cells resulted in a loss of MTS formation. MTS formation allowed MOE PTENshRNA cells to survive better under ultra-low adhesion conditions than control cells. MTS also attached to the ovarian stroma, as would be exposed during ovulation. Interestingly, MTS more robustly cleared monolayers of murine ovarian surface epithelia than murine ovarian fibroblasts. When xenografted into the ovarian bursa, OVCAR8 MTS were able to form tumors in the ovary at a similar rate as an equal number of OVCAR8 cells grown on traditional cell culture plastic. In conclusion, loss of a single gene (PTEN) allows the fallopian tube epithelia to form MTS, which survive better under ultra-low adhesion conditions, attach to the extracellular matrix exposed during ovulation, and colonize the ovary. These results suggest that MTS may contribute to seeding of the ovary in HGSOC patients.
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Anaplastic large cell lymphomas (ALCL) comprise a group of rare, related T-cell neoplasms that typically present on the extremities. Infrequently, cutaneous ALCL can involve the breast, where it is near ubiquitously associated with breast implants. Here, we present the rare case of a 70-year-old woman with primary cutaneous ALCL of the breast with no history of breast augmentation. This serves as an important reminder that in some instances, breast ALCL can be idiopathic. Further, given the potential for malignancy, any changes to the breast skin should be diagnosed quickly in order to ensure rapid delivery of the appropriate treatment.