FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal

Haemmerle, Monika; Bottsford-Miller, Justin; Pradeep, Sunila; Taylor, Morgan; Choi, Hyun Jin; Hansen, Jean M.; Dalton, Heather J.; Stone, Rebecca L.; Cho, Min Soon; Nick, Alpa M.; Nagaraja, Archana S.; Gutschner, Tony; Gharpure, Kshipra M.; Mangala, Lingegowda S.; Rupaimoole, Rajesha; Han, Hee Dong; Zand, Behrouz; Armaiz-Pena, Guillermo N.; Wu, Sherry Y.; Pecot, Chad V.; Burns, Alan R.; López-Berestein, Gabriel; Afshar-Kharghan, Vahid; Sood, Anil K.

doi:10.1172/jci85086

Cited by 104 publications

(106 citation statements)

References 62 publications

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“…The rationale for testing our aspirin test drugs in combination with anti-VEGF drugs was based upon our prior work that demonstrated a key role for platelets in stimulating tumor growth following anti-angiogenesis (8). In addition to the known effect of aspirin on activation of platelets, it has been also reported that most NSAIDs, including aspirin at doses above the COX-1 inhibitory anti-platelet dose have the capacity to inhibit COX-2-mediated prostacyclin production, which appears to be involved in the mechanism of hypoxia–induced angiogenic response in endothelial cells (39–41).…”

Section: Discussionmentioning

confidence: 99%

“…Following initial response to therapy, there is frequently rapid emergence of drug resistance (6, 7). In a recent study, we also demonstrated that platelets play an important role in tumor regrowth following withdrawal of anti-VEGF therapy (8). Though prior studies have mostly focused on associating aspirin use to GI cancer, a number of clinical outcome studies have recently been reported that ovarian cancer is particularly sensitive to chronic consumption of aspirin, with ovarian cancer incidence being significantly reduced in regular users of low dose aspirin (9, 10), though other studies reported aspirin and NSAID use did not provide an effect that reached statistical significance (11).…”

Section: Introductionmentioning

confidence: 88%

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Antitumor and Antiangiogenic Effects of Aspirin-PC in Ovarian Cancer

Huang

Lichtenberger

Taylor

et al. 2016

Molecular Cancer Therapeutics

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To determine the efficacy of a novel and safer (for gastrointestinal tract) aspirin (aspirin-PC) in preclinical models of ovarian cancer, in vitro dose-response studies were performed to compare the growth-inhibitory effect of aspirin-PC vs. aspirin on 3 human (A2780, SKOV3ip1, HeyA8), and a mouse (ID8) ovarian cancer cell line over an 8-day culture period. In the in vivo studies, the aspirin test drugs were studied alone and in the presence of a VEGF-A inhibitor (bevacizumab or B20), due to an emerging role for platelets in tumor growth following anti-angiogenic therapy, and we examined their underlying mechanisms. Aspirin-PC was more potent (vs. aspirin) in blocking the growth of both human and mouse ovarian cancer cells in monolayer culture. Using in vivo model systems of ovarian cancer, we found that aspirin-PC significantly reduced ovarian cancer growth by 50–90% (depending on the ovarian cell line/density). The efficacy was further enhanced in combination with Bevacizumab or B20. The growth-inhibitory effect on ovarian tumor mass and number of tumor nodules was evident, but less pronounced for aspirin and the VEGF inhibitors alone. There was no detectable gastrointestinal toxicity. Both aspirin and aspirin-PC also inhibited cell proliferation, angiogenesis and increased apoptosis of ovarian cancer cells. In conclusion, PC-associated aspirin markedly inhibits the growth of ovarian cancer cells, which exceeds that of the parent drug, in both cell culture and in mouse model systems. We also found that both aspirin-PC and aspirin have robust anti-neoplastic action in the presence of VEGF blocking drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

Antitumor and Antiangiogenic Effects of Aspirin-PC in Ovarian Cancer

Huang

Lichtenberger

Taylor

et al. 2016

Molecular Cancer Therapeutics

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“…However, the lack of nuclei and protein synthesis may limit the distance that platelets migrate because they cannot indefinitely sustain the replacement of proteins [158,159]. Thus platelets may potentially prepare or enable extravasation at secondary metastatic sites [67,248–250,2,130,251]. The use of intravital microscopy coupled with fluorescent platelets is expected to reveal even more details of this rapidly occurring process.…”

Section: Hematogenous Spread Extravasation and Secondary Site Metastmentioning

confidence: 99%

Platelet “first responders” in wound response, cancer, and metastasis

Menter

Kopetz

Hawk

et al. 2017

Cancer Metastasis Rev

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134

111

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Platelets serve as “First Responders” during normal wounding and homeostasis. Arising from bone marrow stem cell lineage megakaryocytes, anucleate platelets can influence inflammation and immune regulation. Biophysically, platelets are optimized due to size and discoid morphology to distribute near vessel walls, monitor vascular integrity and initiate quick responses to vascular lesions. Adhesion receptors linked to a highly reactive filopodia-generating cytoskeleton maximizes their vascular surface contact allowing rapid response capabilities. Functionally, platelets normally initiate rapid clotting, vasoconstriction, inflammation and wound biology that leads to sterilization, tissue repair and resolution. Platelets also are among the first to sense, phagocytize, decorate, or react to pathogens in the circulation. These platelet first responder properties are commandeered during chronic inflammation, cancer progression and metastasis. Leaky or inflammatory reaction blood vessel genesis during carcinogenesis provides opportunities for platelet invasion into tumors. Cancer is thought of as a non-healing or chronic wound that can be actively aided by platelet mitogenic properties to stimulate tumor growth. This growth ultimately outstrips circulatory support leads to angiogenesis and intravasation of tumor cells into the blood stream. Circulating tumor cells reengage additional platelets, which facilitates tumor cell adhesion, arrest and extravasation and metastasis. This process, along with the hypercoagulable states associated with malignancy is amplified by IL6 production in tumors that stimulate liver thrombopoietin production and elevates circulating platelet numbers by thrombopoiesis in the bone marrow. These complex interactions and the “First Responder” role of platelets during diverse physiologic stresses provides a useful therapeutic target that deserves further exploration.

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“…Combination of AAD with chemotherapy demonstrates improvement of survival benefits and is the most commonly used regimen for treatment of most cancer types (18)(19)(20). To maximize AAD clinical benefits, one of the key unresolved issues is to achieve nonstop lifetime therapy in cancer patients because discontinuation of AAD treatment can cause a rebound effect of tumor neovascularization (21)(22)(23)(24). Additionally, withdrawal of AADs might promote cancer metastasis through a vascular recovery mechanism in remote tissues and organs (13).…”

mentioning

confidence: 99%

Maintenance of antiangiogenic and antitumor effects by orally active low-dose capecitabine for long-term cancer therapy

Zhang

Sun

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Significance Withdrawal of antiangiogenic drugs leads to tumor revascularization, even rebound effects of tumor angiogenesis, and potential metastasis. Long-term maintenance therapy with antiangiogenic drugs is crucial for achieving maximal clinical benefits for cancer patients. There are no antiangiogenic drugs that are clinically available for maintenance therapy. We show that orally active capecitabine at an extremely low and nontoxic dose displays a potent antiangiogenic effect that can be used for maintenance therapy. Importantly, the low-dose capecitabine in a sequentially therapeutic setting following anti-VEGF drugs produces remarkable anticancer effects. If successfully proven in clinical settings, our therapeutic regimen would be beneficial for millions of cancer patients. Our findings will shift the paradigm of current antiangiogenic therapy for treatment of human cancer patients.

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FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal

Cited by 104 publications

References 62 publications

Antitumor and Antiangiogenic Effects of Aspirin-PC in Ovarian Cancer

Antitumor and Antiangiogenic Effects of Aspirin-PC in Ovarian Cancer

Platelet “first responders” in wound response, cancer, and metastasis

Maintenance of antiangiogenic and antitumor effects by orally active low-dose capecitabine for long-term cancer therapy

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