Mechanotransduction of fluid stresses governs 3D cell migration

Solid tumors are characterized by high interstitial fluid pressure, which drives fluid efflux from the tumor core. Tumor-associated interstitial flow (IF) at a rate of ∼3 µm/s has been shown to induce cell migration in the upstream direction (rheotaxis). However, the molecular biophysical mechanism that underlies upstream cell polarization and rheotaxis remains unclear. We developed a microfluidic platform to investigate the effects of IF fluid stresses imparted on cells embedded within a collagen type I hydrogel, and we demonstrate that IF stresses result in a transcellular gradient in β1-integrin activation with vinculin, focal adhesion kinase (FAK), FAK^PY397, F actin, and paxillin-dependent protrusion formation localizing to the upstream side of the cell, where matrix adhesions are under maximum tension. This previously unknown mechanism is the result of a force balance between fluid drag on the cell and matrix adhesion tension and is therefore a fundamental, but previously unknown, stimulus for directing cell movement within porous extracellular matrix.Integrins and associated focal adhesion (FA) proteins form a tension-sensitive mechanical link between the extracellular matrix (ECM) and the cytoskeleton, and serve as key components in the signaling cascade by which cells transduce mechanical signals into biological responses (mechanotransduction) (1, 2). Contractile stresses generated by the cell are balanced by tractions at cell–substrate adhesions, and the FA protein vinculin accumulates at regions of high substrate stress (3, 4). The FA protein paxillin colocalizes with vinculin (4) and mediates β1-integrin FA turnover through interaction with FA kinase (FAK) (5). The FAK–paxillin signaling axis recruits vinculin to β1 integrins at regions of high matrix adhesion tension (6), and paxillin—a key mechanosensor (7)—mediates protrusion formation at regions of high stress on 2D substrates (8), and FAK–paxillin–vinculin signaling is required for mechanosensing and durotaxis (9).The tumor microenvironment imparts mechanical and chemical signals on tumor and stromal cells (10), and advanced breast carcinomas are characterized by high interstitial fluid pressure (11), an indicator of poor prognosis (12). This elevated fluid pressure drives interstitial flow (IF) and alters chemical transport within the tumor (13), and IF influences tumor cell migration through the generation of autocrine chemokine gradients (14). Equally important, although not as well understood, is the physical drag imparted on the ECM and constitutive cells (15) by IF, which is analogous to the FA-activating shear stresses generated on endothelial cells by hemodynamic forces (16). With endothelial cells, shear stress can be the dominant mechanical stimulus that induces FAK activation and cytoskeletal remodeling; however, for cells embedded within a porous matrix scaffold, the ratio of the force due to the pressure drop across the cell to the total shear force is inversely proportional to hydrogel permeability (SI Appendix, Eq. S5). In this study, we recapitulate physiologically relevant IF through collagen gel within a microfluidic device. Because the permeability of the collagen I hydrogel used in this study is small (1 × 10⁻¹³ m²), the integrated pressure force is more than 30× the integrated shear force for a 20-μm-diameter cell (17) (SI Appendix, Eq. S5). To maintain static equilibrium, all fluid stresses imparted on the cell must be balanced by tension in matrix adhesions. In 2D, the adhesions balancing the fluid drag on the cell are confined to the basal cell surface, whereas in porous media, such as breast stromal ECM, matrix adhesions are distributed across the full cell surface. Consequently, maintaining static equilibrium requires greater adhesion tension on the upstream side of the cell to balance fluid stresses. From the reference frame of the cell, the effect of IF is mechanically equivalent to applying a net outward force at matrix adhesions on the upstream side of the cell, similar to the net tensile stresses applied by use of optical tweezers to study the molecular mechanisms underlying mechanotransduction (4, 18).Here, we demonstrate that the forces required to balance drag imparted on the cell by IF induce a transcellular gradient in matrix adhesion tension, and the tensile stresses at the upstream side of the cell induce FA reorganization and polarization of FA-plaque proteins including vinculin, paxillin, FAK, FAK^PY397, and α-actinin. FA polarization leads to paxillin-dependent actin localization, the formation of protrusions upstream, and rheotaxis. Consistent with the governing mechanism of durotaxis on 2D substrates, this 3D mechanotransduction occurs through FAK and requires paxillin. Importantly, silencing paxillin does not affect cell migration speed but does attenuate rheotaxis. IF is present in many tissues in vivo (19), and because FA polarization and rheotaxis result from a mechanical force balance, this 3D mechanotransduction mechanism may be fundamental to all cells embedded within porous ECM.     

Central papillary cystadenocarcinoma of the mandible: A case report and review of the literature

INTRODUCTION

Central papillary cystadenocarcinoma of the jaw is an extremely rare tumor with only three previously reported cases in the English literature. This tumor is a histologically low-grade cancer, affecting more commonly in the mandible than in the maxilla.

PRESENTATION OF CASE

A 65-year-old woman presented with a two months history of a rapidly growing, painless mass of the right ascending ramus of the mandible. The pathologic report from incisional biopsy was a papillary cystic tumor with a differential diagnosis of cystadenoma versus cystadenocarcinoma. Segmental mandibulectomy, parotidectomy and submandibular gland resection were performed. The final pathology was intraosseous papillary cystadenocarcinoma.

DISCUSSION

Clinical features of central papillary cystadenocarcinoma of the mandible mimic an odontogenic lesion and metastatic bone disease, careful review of radiograph and pathology should be done. Surgical excision with wide margins is the appropriate treatment. Postoperative radiation therapy should be considered in histologically aggressive or high-stage tumor.

CONCLUSION

This is the fourth case of central papillary cystadenocarcinoma of the mandible in the English literature. Although it is usually a low-grade cancer, en bloc resection with adjuvant postoperative radiotherapy in a high-stage disease, and long-term follow-up allow the patient to have a favorable prognosis.     

High grade angiosarcoma fifteen years after breast conservation therapy with radiation therapy: A case report

INTRODUCTION

Angiosarcoma is a rare tumor of the breast. Secondary angiosarcoma of the breast refers specifically to a tumor that arises after a latency period following radiation. With breast conservation therapy gaining significant popularity to that of mastectomy, more cases of secondary angiosarcoma continue to arise in the irradiated fields of these patients.

PRESENTATION OF CASE

The authors describe the case of an 80 year old female who presented fifteen years after her surgery and radiation treatment with two bleeding skin lesions in her breast. These lesions were found to be high grade angiosarcoma upon excision. Due to high cardiac co-morbidity she was treated with re-excision and surveillance.

DISCUSSION

This case is an example of a rare sequela to a common procedure. Breast conservation therapy with lumpectomy and radiation has become a popular technique in treating localized breast cancer. Radiation like all therapy has its known adverse effects. Further work is needed with the small amount of published cases of angiosarcoma after breast irradiation so that we may find optimal treatment plans for these patients. Like any rare entity, difficulty lies in accruing enough cases to compare prognosis and results.

CONCLUSION

Secondary breast angiosarcoma diagnosis requires frequent follow ups and a high index of suspicion. With mastectomy giving the best chance of treatment in these cases, early detection is crucial in this rare sequela.     

Gastrointestinal bleeding as presentation of small bowel metastases of malignant melanoma: Is surgery a good choice?

INTRODUCTIONMelanoma shows a particular predilection in involving small intestine both in a single site and in multiple localization and acute or chronic gastrointestinal bleedings are often the first sign of tumour.PRESENTATION OF CASEWe report two cases of GI metastases of malignant melanoma, one presented with only a big mass that cause intestinal obstruction and the other with a tumour spread throughout the small intestine that produce enterorrhagia.DISCUSSIONDiagnosis and follow-up are very difficult: CT scan, PET-CT scan and capsule endoscopy should be complementary for the assessment of patients with GI symptoms and melanoma history.CONCLUSIONWhat is the role of surgery? Several studies suggest metastasectomy to achieve both R0 results and palliative resolutions of acute symptoms, such as obstruction, pain, and bleeding.     

窄带成像结合放大内镜对110例结肠息肉的观察分析

目的运用窄带成像(NBI)结合放大内镜对结肠息肉进行观察分析,比较其在腺管开口形态及病理学类型的差异。方法肠息肉患者110例,共留取147个病理组织学活检样本,利用NBI结合放大内镜技术观察结肠息肉腺管开口类型、微血管形态与肿瘤性息肉的关系,并与病理组织学比较,分析肿瘤性息肉的诊断符合率、敏感性及特异性。结果肿瘤性息肉的腺管分型多为Ⅲ、Ⅳ、Ⅴ型。对肿瘤性息肉的诊断符合率、敏感性及特异性(91.16%、88.37%、95.08%)均高于普通肠镜(80.27%、79.07%、81.97%),且NBI放大内镜诊断上皮内瘤变及早癌的准确率也明显高于普通内镜,差异均有统计学意义。结论 NBI结合放大内镜能更清楚地观察到息肉表面的腺管开口及表面微血管形态,有利于结肠息肉样肿瘤性病变的诊断。