Antibody drug conjugates (ADCs) are effective for tumors with no or little stroma, such as malignant lymphoma or breast cancer. However, in refractory cancers (pancreatic cancer or scirrhous gastric cancer) forming hypovascular and stroma-rich tumors, the penetration of monoclonal antibodies (mAbs) into the cells is impeded (stromal barrier), which leads to failure of conventional cell-targeting ADCs. To overcome this, we developed cancer stromal targeting (CAST) therapy using anti-collagen IV or anti-fibrin mAbs. These stroma-targeting ADCs selectively extravasated from leaky tumor vessels and bound to collagen IV or fibrin on the tumor stroma, from which effective sustained release of the payload drug occurred. The released drug subsequently diffused through the tumor tissue, causing marked arrest of tumor growth associated with damage to tumor vessels and death of cancer cells. In terms of the pathological findings after treatment, empty sleeves collagen IV-positive and CD31-negative remnant ring structures) were observed in the destroyed vessels. This review highlights the tumor stromal barrier and the development of CAST therapy. Insights into the pharmacokinetics and efficacy of antibodies or ADCs may also be informative to understand the pathophysiological role of the tumor microcirculation involved in the stromal barrier.
Magnifying endoscopy with narrow-band imaging (ME-NBI) enhances visualization of microcirculatory and micromucosal structures for a more detailed assessment of gastrointestinal cancer. The updated Japan esophageal society classification is simple and useful for diagnosing esophageal squamous cell cancer and the depth of invasion. In ME-NBI of gastric tumors, an irregular microvascular pattern and the presence of a demarcation line are characteristic signs of early gastric cancer. A relatively regular “fine network pattern” or an abundant microvessel “mesh pattern” is more likely observed in well-differentiated adenocarcinoma. Tortuous microvessels and a low-density microvessel “corkscrew pattern” are more likely observed in poorly differentiated adenocarcinoma. In ME-NBI of colonic tumors, the vague microvascular pattern is often observed in hyperplastic polyps. The regular meshed microvascular pattern is most frequently observed in adenomas. The irregular meshed microvascular pattern is often observed in intramucosal or relatively shallow submucosal invasive carcinomas. The irregular and loose microvascular pattern is often observed in deeply invasive submucosal carcinomas.
Chronic hypoxia provokes morphological and functional adaptations of the brain microcirculaton, such as angiogenesis and regulation of blood flow. In the mouse cortex, parenchymal capillary significantly dilates after 1-week hypoxia to facilitate an exchange of oxygen with tissue. A vessel sprout appears during 1-2 week hypoxia and creates a new vessel connection. A net contribution of the new vessels to the oxygen delivery may be limited, but effective for a local spot of oxygen deficiency. Because brain vasculature is surrounded with a variety of cells, such as pericytes, astrocytes, and microglias, these perivascular cells may participate in a process of the angiogenesis differently at each step; sprout, extension, connection, and normalization. Depending on cell types, oxygen environment may not be uniform as variable distances from the nearest vasculature. This indicates that the mechanism for oxygen sensing in the cells might not necessarily be common among the cells. Chronic hypoxia attenuates the response of the cortical arteries to neural activation, leading to a reduction of activity-dependent blood flow increases. This adaptation might be important for further understanding the role of neurovascular coupling in maintaining the functional plasticity of the central nervous system.
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