Microfluidic modelling of the tumor microenvironment for anti-cancer drug development

In the paper

“Through this, it was shown that adenosine played an important role in promoting tumor cells extravasation.”

What the sources say

• Disputed

  The Results (p. 5) report that adding adenosine significantly reduced cancer cell extravasation, from 56.5% to 12.7%, rather than promoting it. The Fig. 3 caption (p. 6) confirms that extravasation decreased with adenosine. (LLM, conf=0.94)

  Checked by a reasoning model — may be wrong.

  cites [98] 98. Jeon, J.S., et al., Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. Proceedings of the National Academy of Sciences, 2015. 112(1): p. 214-219. sourceExperimental — accuracy not yet measured

In the paper

“By blocking A3 adenosine receptors, cancer cells were observed to have a reduced extravasation rate.”

What the sources say

• Disputed

  The Results (p. 5) report the opposite effect: blocking A3 adenosine receptors with PSB-10 significantly increased cancer cell extravasation in C2C12-containing matrices, from 8.2 ± 2.3% to 32.4 ± 7.7%. The Fig. 3 caption (p. 6) also states that extravasation increased with receptor blockade. (LLM, conf=0.95)

  Checked by a reasoning model — may be wrong.

  cites [98] 98. Jeon, J.S., et al., Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. Proceedings of the National Academy of Sciences, 2015. 112(1): p. 214-219. sourceExperimental — accuracy not yet measured

In the paper

“The uniformly elevated IFP in tumor center is responsible for inhibiting drug delivery [172, 178, 186] while the steep pressure gradients at the periphery favors tumor growth and metastasis[154,[187][188][189][190].”

What the sources say

• Disputed

  The Introduction (page unavailable) links elevated tumor pressure to outward interstitial flow, but does not identify steep gradients at the tumor periphery or show that they favor growth. More importantly, the Results and Discussion (page unavailable) report that, despite increasing cell speed, flow impaired the cells’ ability to spread to a distant site—the opposite of the claimed effect on metastasis. (LLM, conf=0.85)

  Checked by a reasoning model — may be wrong.

  cites [154] sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction says pressure falls sharply at the tumor margin, creating fluid flow that transports molecules and cells facilitating angiogenesis and metastasis. The Mathematical model section says less steep gradients could potentially reduce lymphatic metastasis. The paper does not explicitly link the peripheral gradient to tumor growth, and presents its effect on metastasis as a proposed mechanism rather than an established outcome. (LLM, conf=0.84)

  cites [187] sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction says interstitial fluid pressure may stretch the tumor cortex and thereby promote proliferation; the Discussion reports that lowering pressure reduced proliferation in a xenograft model. The Discussion also describes pressure falling from the tumor core toward the cortex. Neither passage establishes that steep peripheral pressure gradients favor metastasis, and the growth finding concerns pressure-induced stretch rather than the gradient itself. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  cites [188] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [189] source
• Partly supported

  The Results and the discussion on p. 2395 report that elevated pressure affected osteosarcoma-cell proliferation, with growth increasing in some cell lines and being suppressed in others. The paper does not show that steep pressure gradients at the tumor periphery favor growth, and it does not link those gradients to metastasis. (LLM, conf=0.84)

  cites [190] sourceExperimental — accuracy not yet measured

In the paper

“Over the years, research has demonstrated that the tumor microenvironment plays a key role in this process [3,6,7].”

What the sources say

• ?Not checked — no full text of the sourcecites [3] 3. Hanahan, D. and R.A. Weinberg, Hallmarks of cancer: The next generation. Cell, 2011. 144(5): p. 646-674. source
• ?Not checked — no full text of the sourcecites [6] 6. Kessenbrock, K., V. Plaks, and Z. Werb, Matrix Metalloproteinases: Regulators of the Tumor Microenvironment. Cell, 2010. 141(1): p. 52-67. source
• Supported

  The opening section (p. 1) states that inflammation in the tumour microenvironment promotes metastasis. The section on invasion and metastasis (p. 5) further describes how inflammatory cells and mediators contribute to malignant-cell migration, invasion and metastasis. (LLM, conf=0.93)

  cites [7] 7. Mantovani, A., et al., Cancer-related inflammation. Nature, 2008. 454(7203): p. 436-444. source

In the paper

“In the former, due to the physical contact between cells, this allows for the study of adhesion molecules such as Ncadherins [50].”

What the sources say

• Partly supported

  The sections “The normal epithelial ecosystem” and “The cancer ecosystem” describe co-culture systems and direct cell–cell contacts. “Molecular mechanisms of N-cadherin-mediated invasion and migration” links N-cadherin to cell–cell contact, but the paper does not say that direct co-culture is used to study adhesion molecules such as N-cadherin. (LLM, conf=0.83)

  cites [50] 50. De Wever, O. and M. Mareel, Role of tissue stroma in cancer cell invasion. The Journal of Pathology, 2003. 200(4): p. 429-447. sourceExperimental — accuracy not yet measured

In the paper

“The ECM is known to influence cell behavior in terms of cell migration, and anchorage, by serving as a medium to transmit external forces from environmental cues and even cell signaling throughout the entire lifespan of the cell and at critical phases in their lives [19,20].”

What the sources say

• Supported

  The Introduction says the ECM provides substrates for cell motility, supports cell adhesion, and signals to cells through adhesion receptors. It also says matrix stiffness and deformability provide inputs into cell behavior, and that cells contact the ECM either continuously or at important developmental phases. (LLM, conf=0.91)

  cites [19] 19. Hynes, R.O., The Extracellular Matrix: Not Just Pretty Fibrils. Science, 2009. 326(5957): p. 1216-1219. source
• Supported

  The “Properties and features of the ECM” section (page not provided) describes the ECM as an anchorage site or movement track that affects cell migration. It also explains how ECM elasticity shapes cells’ responses to external forces and how the ECM regulates signaling and cell behavior. (LLM, conf=0.90)

  cites [20] 20. Lu, P., V.M. Weaver, and Z. Werb, The extracellular matrix: A dynamic niche in cancer progression. Journal of Cell Biology, 2012. 196(4): p. 395-406. source

In the paper

“For example, by studying the genetic alterations in the tumor cells, the events through which the stroma affects cancer cells can be elucidated [48].”

What the sources say

• Partly supported

  The Abstract says that the molecular events through which reactive stromal cells affect cancer cells can be defined. Section 2.5 discusses genetic changes within tumor cells, but does not say that studying those changes is how stromal effects can be elucidated. The cited paper therefore supports the outcome, not the proposed method. (LLM, conf=0.87)

  cites [48] 48. Mao, Y., et al., Stromal cells in tumor microenvironment and breast cancer. Cancer and Metastasis Reviews, 2013. 32(1-2): p. 303-315. sourceExperimental — accuracy not yet measured

In the paper

“In the latter, signaling pathways between the different types of cells such as cancer cells and fibroblasts can be better studied [51].”

What the sources say

• Partly supported

  Section 2.1 describes indirect transwell cocultures used to examine gene-expression responses between breast cancer cells and fibroblasts, including changes in a signaling pathway. It does not establish that signaling pathways are generally better studied in indirect than in direct coculture; it notes that direct contact can produce distinct profiles, although separating the cells requires additional steps. Page numbers were not provided in our copy. (LLM, conf=0.78)

  cites [51] 51. Casbas-Hernandez, P., J.M. Fleming, and M.A. Troester, Gene Expression Analysis of In Vitro Cocultures to Study Interactions between Breast Epithelium and Stroma. Journal of Biomedicine and Biotechnology, 2011. 2011: p. 1-12. sourceExperimental — accuracy not yet measured

In the paper

“As a tumor will be cultivated in vivo within these animals, it is also able to better mimic the molecular and histopathological features of cancer [40,41].”

What the sources say

• Partly supported

  The Abstract (p. 1) says tumors arising in advanced genetically engineered mouse models closely mimic the histopathological and molecular features of human cancers. The claim extends that finding to tumors cultivated in vivo in animals generally, but the Xenotransplantation section (p. 3) says in vivo cell-line inoculation models do not reflect the morphology and genetic heterogeneity of human cancers. (LLM, conf=0.88)

  cites [40] 40. Kersten, K., et al., Genetically engineered mouse models in oncology research and cancer medicine. EMBO Molecular Medicine, 2017. 9(2): p. 137-153. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [41] 41. Singh, M., C.L. Murriel, and L. Johnson, Genetically engineered mouse models: Closing the gap between preclinical data and trial outcomes. Cancer Research, 2012. 72(11): p. 2695- 2700. source

In the paper

“Conversely, the reproducibility of a tumor also becomes an issue since a tumor is highly heterogeneous and varies not only between patients but also between different tumors or even within the same tumor inside an individual patient [38].”

What the sources say

• Partly supported

  The Abstract describes heterogeneity between tumours and within individual tumours, and “Clinical Implications of ITH > A. Tumour Sampling Bias” explains how variation between sampled sites can complicate biomarker validation. The paper does not specifically address the reproducibility of tumour explants, so that application goes beyond what our copy establishes. (LLM, conf=0.83)

  cites [38] 38. Swanton, C., Intratumor Heterogeneity: Evolution through Space and Time. Cancer Research, 2012. 72(19): p. 4875-4882. sourceExperimental — accuracy not yet measured

In the paper

“The overexpression of these collagens leads to the formation of a stiffer ECM which in turn promotes the formation of a tumorigenic microenvironment [26].”

What the sources say

• Supported

  The 'Increased deposition and cross-linking of collagens' section says increased collagen deposition and ECM remodeling create a microenvironment that promotes tumor progression. The 'Tension homeostasis and tumor progression' section says ECM protein deposition and matrix cross-linking can stiffen tissue. Together, these support the paraphrased claim; page numbers were not available in our copy. (LLM, conf=0.88)

  cites [26] 26. Fang, M., et al., Collagen as a double-edged sword in tumor progression. Tumour Biology, 2014. 35(4): p. 2871-2882. source

In the paper

“Such heterogeneity is observed in the cohort of circulating tumor cells (CTCs) [12,13], which can be isolated from the peripheral bloodstream or cultured for further analyses.”

What the sources say

• Supported

  The Discussion explicitly refers to “heterogeneous CTCs” and explains that detection markers do not apply to all CTC subpopulations. It also describes differences in their epithelial and mesenchymal characteristics, supporting the claim that CTCs are heterogeneous. (LLM, conf=0.94)

  cites [12] 12. Khoo, B.L., et al., Liquid biopsy and therapeutic response: Circulating tumor cell cultures for evaluation of anticancer treatment. Science Advances, 2016. 2(e1600274). source
• Supported

  The Discussion explicitly states that CTCs are a heterogeneous population (passage 4). The Methods describe collecting peripheral blood for CTC analysis (passage 8), and the Results describe generating and culturing CTC lines (passages 5–6). (LLM, conf=0.94)

  cites [13] 13. Zhang, L., et al., The identification and characterization of breast cancer CTCs competent for brain metastasis. Sci Transl Med, 2013. 5(180): p. 180ra48. source

In the paper

“It was shown that human non-small cell lung cancer cells (PC9) cultured in their devices had stronger drug resistance to four different apoptotic inducers than two-dimensional cultured PC9 cells.”

What the sources say

• Supported

  The Experimental Section identifies four apoptotic inducers tested on PC9 cells in conventional dishes and the 3D device. The Discussion reports that static 3D PC9/HMVEC cocultures responded similarly to 2D monolayers, while responses in the device were reduced and delayed relative to static cocultures. This supports stronger drug resistance in the device, as measured by reduced caspase-3 response. (LLM, conf=0.85)

  cites [81] 81. Dereli-Korkut, Z., et al., Three dimensional microfluidic cell arrays for ex vivo drug screening with mimicked vascular flow. Analytical Chemistry, 2014. 86(6): p. 2997-3004. source

In the paper

“Furthermore, 2D cultured cells are artificially polarized when their cytoskeleton rearranges as they are stretched on the culture plate, which in turn causes these cultured cells to express genes and proteins which are atypical [56].”

What the sources say

• Supported

  The Introduction directly states that 2D-cultured cells are stretched, undergo cytoskeletal rearrangements, acquire artificial polarity, and consequently show aberrant gene and protein expression. This supports the citing sentence’s paraphrase. (LLM, conf=0.94)

  cites [56] 56. Nath, S. and G.R. Devi, Three-dimensional culture systems in cancer research: Focus on tumor spheroid model. Pharmacology and Therapeutics, 2016. 163: p. 94-108. source

In the paper

“Specifically, the location of focal adhesions and the various cell surface proteins such as integrin and their binding has been demonstrated to be markedly different from their original 3D form [54,55].”

What the sources say

• ?Not checked — no full text of the sourcecites [54] 54. Cukierman, E., et al., Taking Cell-Matrix Adhesions to the Third Dimension. Science, 2001. 294(5547): p. 1708-1712. source
• Partly supported

  The Introduction (page unavailable) says that focal adhesions contain integrins and that ligand binding controls integrin localization within them. It does not demonstrate that focal adhesion locations, cell-surface proteins, or their binding differ markedly from an original 3D form. (LLM, conf=0.82)

  cites [55] 55. Gumbiner, B.M., Cell adhesion: The molecular basis of tissue architecture and morphogenesis. Cell, 1996. 84(3): p. 345-357. sourceExperimental — accuracy not yet measured

In the paper

“In recent years, techniques which can overcome the abnormal vasculature in the tumor, such as nanoparticle drug delivery and drugs normalizing vascular network, were shown to be able to greatly improve anti-cancer treatment [108-113].”

What the sources say

• ?Not checked — no full text of the sourcecites [108] 108. Trietsch, S.J., et al., Microfluidic titer plate for stratified 3D cell culture. Lab on a Chip, 2013. 13(18): p. 3548-3554. 132. Napolitano, A., et al., Scaffold-free three-dimensional cell culture utilizing micromolded nonadhesive hydrogels. BioTechniques, 2007. 43(4): p. 494-500. 133. Xu, Z., et al., Application of a microfluidic chip-based 3D co-culture to test drug sensitivity for individualized treatment of lung cancer. Biomaterials, 2013. 34(16): p. 4109-17. 134. Zhang, Z., et al., Expansion of CTCs from early stage lung cancer patients using a microfluidic co-culture model. Oncotar source
• ?Not checked — no full text of the sourcecites [109] 109. Choi, Y., et al., A microengineered pathophysiological model of early-stage breast cancer. Lab on a Chip, 2015. 15(16): p. 3350-7. 137. Ke, L.-Y., et al., Cancer immunotherapy μ-environment LabChip: taking advantage of optoelectronic tweezers. Lab on a Chip, 2018. 18(1): p. 106-114. 138. Huh, D., et al., A human disease model of drug toxicity-induced pulmonary edema in a lung- on-a-chip microdevice. Science translational medicine, 2012. 4(159): p. 159ra147-159ra147. 139. source
• ?Not checked — no full text of the sourcecites [110] 110. Bender, B.F., A.P. Aijian, and R.L. Garrell, Digital microfluidics for spheroid-based invasion assays. Lab on a Chip, 2016. 16(8): p. 1505-13. 140. Shin, Y., et al., Microfluidic assay for simultaneous culture of multiple cell types on surfaces or within hydrogels. Nature protocols, 2012. 7(7): p. 1247-59. 141. Kim, J.Y., et al., 3D spherical microtissues and microfluidic technology for multi-tissue experiments and analysis. Journal of biotechnology, 2015. 205: p. 24-35. 142. Menon, N.V., et al., A microfluidic co-culture system to monitor tumor-stromal interactions on a chip. Biomicroflu source
• ?Not checked — no full text of the sourcecites [111] 111. Avvisato, C.L., et al., Mechanical force modulates global gene expression and β-catenin signaling in colon cancer cells. J Cell Sci, 2007. 120(15): p. 2672-2682. 151. Swartz, M.A. and A.W. Lund, Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nature reviews. Cancer, 2012. 12(3): p. 210-9. 152. source
• ?Not checked — no full text of the sourcecites [112] 112. Song, J.W. and L.L. Munn, Fluid forces control endothelial sprouting. Proceedings of the National Academy of Sciences, 2011. 108(37): p. 15342-15347. 153 source
• ?Could not verify

  The Abstract and Discussion describe how circulatory shear stress affects colon cancer cell viability and proliferation, not treatments that overcome abnormal tumor vasculature. Searches for nanoparticle drug delivery and vascular normalization found no passage addressing whether those techniques improve anti-cancer treatment; no page numbers are available in our copy. (LLM, conf=0.75)

  cites [113] 113. Fan, R., et al., Circulatory shear flow alters the viability and proliferation of circulating colon cancer cells. Scientific reports, 2016. 6: p. 27073. 154. Huang, Y.L., et al., Interstitial flows promote amoeboid over mesenchymal motility of breast cancer cells revealed by a three dimensional microfluidic model. Integrative Biology, 2015. sourceExperimental — accuracy not yet measured

In the paper

“The blood circulation system is also a key component in metastasis because many malignant cells migrate as circulating cancer cells through blood vessels [105].”

What the sources say

• ?Could not verify

  The sections on tumor heterogeneity discuss differences between primary tumors and metastases, and the section on epigenetic alterations mentions migratory capabilities. Neither addresses whether malignant cells travel through blood vessels as circulating cancer cells or establishes the blood circulation system’s role in metastasis. Searches for circulating tumor cells, blood vessels, bloodstream, and vascular dissemination found no supporting passage. (LLM, conf=0.76)

  cites [105] 105. Easwaran, H., H.-C. Tsai, and S.B. Baylin, Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Molecular cell, 2014. 54(5): p. 716-727. 121. sourceExperimental — accuracy not yet measured

In the paper

“Endothelial cells, fibroblasts, and immune cells are the three main cell types which appear in most cancers and are vital components in enhancing the drug resistance of tumors [103, 114-120].”

What the sources say

• ?Not checked — no full text of the sourcecites [103] 103. Sun, T., et al., Engineered nanoparticles for drug delivery in cancer therapy. Angewandte Chemie International Edition, 2014. 53(46): p. 12320-12364. 113. source
• ?Not checked — no full text of the sourcecites [114] 114. 11): p. 1402-1411. 155. Astolfi, M., et al., Micro-dissected tumor tissues on chip: an ex vivo method for drug testing and personalized therapy. Lab on a Chip, 2016. 16(2): p. 312-325. 156. source
• ?Could not verify

  The Abstract and Discussion address chemoresistance in ovarian cancer cells under fluid shear stress, not the cellular composition of most cancers. Searches for endothelial cells, fibroblasts, immune cells, and stromal cell types found no passage identifying them as the three main non-neoplastic cell types. (LLM, conf=0.76)

  cites [115] 115. Ip, C.K., et al., Stemness and chemoresistance in epithelial ovarian carcinoma cells under shear stress. Scientific reports, 2016. 6: p. 26788. 157. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page unavailable) identifies fibroblasts and infiltrating immune cells as surrounding non-tumor cells involved in tumor progression. The paper also studies endothelial cells and fibroblasts, but it does not say these three are the main non-neoplastic cell types in most cancers or establish the citing sentence’s drug-resistance claim. (LLM, conf=0.86)

  cites [116] 116. Alonzo, L.F., et al., Microfluidic device to control interstitial flow-mediated homotypic and heterotypic cellular communication. Lab on a Chip, 2015. 15(17): p. 3521-9. 158. Oh, J., et al., Analytical cell adhesion chromatography reveals impaired persistence of metastatic cell rolling adhesion to P-selectin. Journal of cell science, 2015. 128(20): p. 3731- 43. 159. Calibasi Kocal, G., et al., Dynamic Microenvironment Induces Phenotypic Plasticity of Esophageal Cancer Cells Under Flow. Scientific reports, 2016. 6: p. 38221. 160. Kang, T., C. Park, and B.J. Lee, Investigation of biomimetic sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [117] 117. Trietsch, S.J., et al., Microfluidic titer plate for stratified 3D cell culture. Lab on a Chip, 2013. 13(18): p. 3548-54. 163. Khoo, B.L., et al., Expansion of patient-derived circulating tumor cells from liquid biopsies using a CTC microfluidic culture device. Nat Protoc, 2018. 13(1): p. 34-58. 164. Businaro, L., et al., Cross talk between cancer and immune cells: exploring complex dynamics in a microfluidic environment. Lab on a Chip, 2013. 13(2): p. 229-239. 165. Holton, A.B., et al., Microfluidic Biopsy Trapping Device for the Real-Time Monitoring of Tumor Microenvironment. PLoS One, source
• ?Not checked — no full text of the sourcecites [118] 118. Douville, N.J., et al., Combination of fluid and solid mechanical stresses contribute to cell death and detachment in a microfluidic alveolar model. Lab on a Chip, 2011. 11(4): p. 609- 19. 167. Piotrowski-Daspit, A.S., J. Tien, and C.M. Nelson, Interstitial fluid pressure regulates collective invasion in engineered human breast tumors via Snail, vimentin, and E-cadherin. Integrative biology : quantitative biosciences from nano to macro, 2016. 8(3): p. 319-31. 168. Polacheck, W.J., et al., Mechanotransduction of fluid stresses governs 3D cell migration. Proceedings of the National Academy source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [119] 119. Less, J.R., et al., Interstitial hypertension in human breast and colorectal tumors. Cancer research, 1992. 52(22): p. 6371-6374. 173. Curti, B.D., et al., Interstitial pressure of subcutaneous nodules in melanoma and lymphoma patients: changes during treatment. Cancer research, 1993. 53(10): p. 2204-2207. 174. Gutmann, R., et al., Interstitial hypertension in head and neck tumors in patients: correlation with tumor size. Cancer research, 1992. 52(7): p. 1993-1995. 175. Griffon-Etienne, G., et al., Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure
• ?Not checked — no full text of the sourcecites [120] 120. Wilson, W.R. and M.P. Hay, Targeting hypoxia in cancer therapy. Nature Reviews Cancer, 2011. 11(6): p. 393. 184. Carmeliet, P. and R.K. Jain, Molecular mechanisms and clinical applications of angiogenesis. Nature, 2011. 473(7347): p. 298-307. 185. source

In the paper

“By using this microfluidic device, it was shown that CAFs might promote NSCLC cell invasion by up-regulation of GRP78 expression.”

What the sources say

• Supported

  The Abstract explicitly concludes that CAFs might promote NSCLC cell invasion by up-regulating GRP78 expression. The Results sections report that CAF-conditioned medium increased GRP78 expression in A549 and SPCA-1 cells and that GRP78 knockdown reduced their migration and invasion in the microdevice. (LLM, conf=0.95)

  cites [143] source

In the paper

“Formation of cell clusters in the microwells was shown to be inversely correlated with increased drug concentration and therapeutic treatment and this liquid biopsy technique can potentially be used to develop personalized medicine.”

What the sources say

• Supported

  The Results report that the percentage of microwells with clusters decreased as doxorubicin concentration increased, and that CTC-containing cluster formation appeared to correlate negatively with patient response. The Discussion also reports fewer positive cluster cultures in posttreatment than pretreatment samples (19.6% versus 59.3%). (LLM, conf=0.91)

  cites [135] source

In the paper

“Immune cells were shown to both enhance and inhibit malignant cells proliferation, migration, and metastasis [125-128].”

What the sources say

• ?Not checked — no full text of the sourcecites [125] 125. Weigelt, B., J.L. Peterse, and L.J. Van't Veer, Breast cancer metastasis: markers and models. Nature reviews cancer, 2005. 5(8): p. 591. 197. Muz, B., et al., The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia, 2015. 3: p. 83. 198. source
• ?Not checked — no full text of the sourcecites [126] 126. Kamei, K.-i., et al., 3D printing of soft lithography mold for rapid production of polydimethylsiloxane-based microfluidic devices for cell stimulation with concentration gradients. Biomedical microdevices, 2015. 17(2): p. 36. 199. source
• ?Could not verify

  Section 2.3 discusses cancer-cell migration in the metastatic cascade and responses to chemical gradients, but does not address immune cells enhancing or inhibiting malignant-cell proliferation, migration, or metastasis. Searches for immune-cell effects and tumor proliferation found no passage supporting the attributed point; no page number was provided in our copy. (LLM, conf=0.76)

  cites [127] 127. Uzel, S.G., et al., Simultaneous or Sequential Orthogonal Gradient Formation in a 3D Cell Culture Microfluidic Platform. Small, 2016. 12(5): p. 612-22. 200. sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [128] 128. Al-Abboodi, A., et al., In situ generation of tunable porosity gradients in hydrogel-based scaffolds for microfluidic cell culture. Adv Healthc Mater, 2014. 3(10): p. 1655-70. 201. Del Amo, C., et al., Quantifying 3D chemotaxis in microfluidic-based chips with step gradients of collagen hydrogel concentrations. Integr Biol (Camb), 2017. 9(4): p. 339-349. 202. Zou, H., et al., Microfluidic Platform for Studying Chemotaxis of Adhesive Cells Revealed a Gradient-Dependent Migration and Acceleration of Cancer Stem Cells. Anal Chem, 2015. 87(14): p. 7098-108. 203. Wang, H., et al., A convection

In the paper

“Formation of cell clusters in the microwells was shown to be inversely correlated with increased drug concentration and therapeutic treatment and this liquid biopsy technique can potentially be used to develop personalized medicine.”

What the sources say

• Supported

  The Discussion describes the microwell-based liquid-biopsy assay as a potential way to assess drug response and guide therapeutic choices for personalized treatment. It also says routine assessment of serial clinical samples could eventually enable personalized treatment. Page numbers were not provided in the supplied passages. (LLM, conf=0.93)

  cites [135] source

In the paper

“Endothelial cells, fibroblasts, and immune cells are the three main cell types which appear in most cancers and are vital components in enhancing the drug resistance of tumors [103, 114-120].”

What the sources say

• ?Not checked — no full text of the sourcecites [103] 103. Sun, T., et al., Engineered nanoparticles for drug delivery in cancer therapy. Angewandte Chemie International Edition, 2014. 53(46): p. 12320-12364. 113. source
• ?Not checked — no full text of the sourcecites [114] 114. 11): p. 1402-1411. 155. Astolfi, M., et al., Micro-dissected tumor tissues on chip: an ex vivo method for drug testing and personalized therapy. Lab on a Chip, 2016. 16(2): p. 312-325. 156. source
• ?Could not verify

  The Results and Discussion passages attribute increased chemoresistance in ovarian cancer spheroids to fluid shear stress, not to endothelial cells, fibroblasts, or immune cells. Searches for those three cell types and for stromal cells enhancing chemoresistance found no passage in our copy supporting the attributed claim; page numbers were unavailable. (LLM, conf=0.76)

  cites [115] 115. Ip, C.K., et al., Stemness and chemoresistance in epithelial ovarian carcinoma cells under shear stress. Scientific reports, 2016. 6: p. 26788. 157. sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Introduction links fibroblasts and infiltrating immune cells to tumor progression, and the Discussion describes endothelial-cell vessel formation. Neither passage addresses whether these three cell types enhance tumor drug resistance; searches for drug resistance and treatment found no such passage in our copy. (LLM, conf=0.76)

  cites [116] 116. Alonzo, L.F., et al., Microfluidic device to control interstitial flow-mediated homotypic and heterotypic cellular communication. Lab on a Chip, 2015. 15(17): p. 3521-9. 158. Oh, J., et al., Analytical cell adhesion chromatography reveals impaired persistence of metastatic cell rolling adhesion to P-selectin. Journal of cell science, 2015. 128(20): p. 3731- 43. 159. Calibasi Kocal, G., et al., Dynamic Microenvironment Induces Phenotypic Plasticity of Esophageal Cancer Cells Under Flow. Scientific reports, 2016. 6: p. 38221. 160. Kang, T., C. Park, and B.J. Lee, Investigation of biomimetic sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [117] 117. Trietsch, S.J., et al., Microfluidic titer plate for stratified 3D cell culture. Lab on a Chip, 2013. 13(18): p. 3548-54. 163. Khoo, B.L., et al., Expansion of patient-derived circulating tumor cells from liquid biopsies using a CTC microfluidic culture device. Nat Protoc, 2018. 13(1): p. 34-58. 164. Businaro, L., et al., Cross talk between cancer and immune cells: exploring complex dynamics in a microfluidic environment. Lab on a Chip, 2013. 13(2): p. 229-239. 165. Holton, A.B., et al., Microfluidic Biopsy Trapping Device for the Real-Time Monitoring of Tumor Microenvironment. PLoS One, source
• ?Not checked — no full text of the sourcecites [118] 118. Douville, N.J., et al., Combination of fluid and solid mechanical stresses contribute to cell death and detachment in a microfluidic alveolar model. Lab on a Chip, 2011. 11(4): p. 609- 19. 167. Piotrowski-Daspit, A.S., J. Tien, and C.M. Nelson, Interstitial fluid pressure regulates collective invasion in engineered human breast tumors via Snail, vimentin, and E-cadherin. Integrative biology : quantitative biosciences from nano to macro, 2016. 8(3): p. 319-31. 168. Polacheck, W.J., et al., Mechanotransduction of fluid stresses governs 3D cell migration. Proceedings of the National Academy source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [119] 119. Less, J.R., et al., Interstitial hypertension in human breast and colorectal tumors. Cancer research, 1992. 52(22): p. 6371-6374. 173. Curti, B.D., et al., Interstitial pressure of subcutaneous nodules in melanoma and lymphoma patients: changes during treatment. Cancer research, 1993. 53(10): p. 2204-2207. 174. Gutmann, R., et al., Interstitial hypertension in head and neck tumors in patients: correlation with tumor size. Cancer research, 1992. 52(7): p. 1993-1995. 175. Griffon-Etienne, G., et al., Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure
• ?Not checked — no full text of the sourcecites [120] 120. Wilson, W.R. and M.P. Hay, Targeting hypoxia in cancer therapy. Nature Reviews Cancer, 2011. 11(6): p. 393. 184. Carmeliet, P. and R.K. Jain, Molecular mechanisms and clinical applications of angiogenesis. Nature, 2011. 473(7347): p. 298-307. 185. source

In the paper

“Due to the presence of interstitial flow in tumors, there is a corresponding fluid shear stress with a magnitude of approximately 0.1 dyn 𝑐𝑚 -2 [149].”

What the sources say

• Partly supported

  The ‘Fluid Shear Stress Exposure in the Tumor Microenvironment’ section says interstitial flow generates cell-surface shear stress believed to be on the order of 0.1 dyn cm−2. It does not establish that magnitude specifically for tumors; the same section says interstitial flows can be significantly elevated in tumors. Page numbers are unavailable in our copy. (LLM, conf=0.84)

  cites [149] sourceExperimental — accuracy not yet measured

In the paper

“They demonstrated the change in 88 metabolites during cellular adaptation to hypoxia gradient and found that cell metabolism was deregulated in the absence of HIF.”

What the sources say

• Partly supported

  The 'Metabolomic signature mapping in 3D' section says 88 metabolites were analyzed, but only 23 showed a significant correlation with hypoxia in control cells; it does not report changes in all 88. The 'HIF-dependent and HIF-independent metabolic signatures' section reports changes in several metabolites in HIF-knockdown cells, but the Outlook says changes in glycolysis and mitochondrial metabolism were largely HIF-independent. Thus the broad statement that cell metabolism was deregulated in the absence of HIF overstates the findings. (LLM, conf=0.88)

  cites [216] sourceExperimental — accuracy not yet measured

In the paper

“Different from these engineering approaches, some recent works adopted 3D tissue structures to reconstitute the oxygen gradient in the tumor [215, 216].”

What the sources say

• Supported

  The paper describes its use of 3D tumor spheroids and states that spheroids have oxygen gradients along their radius, mimicking an avascular solid tumor (Introduction passage supplied under Abstract). The Discussion also says oxygen tension is lower within a spheroid because diffusion is limited and cells consume oxygen. (LLM, conf=0.90)

  cites [215] source
• Supported

  The Abstract describes a three-dimensional tumour model assembled by rolling a scaffold–tumour strip and says that oxygen gradients form within it. The section ‘Oxygen gradient dynamics reveal HIF-dependent adaptations’ states that the model establishes oxygen gradients from normoxia to severe hypoxia, as observed in tumours. (LLM, conf=0.94)

  cites [216] source

In the paper

“By observing cell behavior in these devices, it was found that different types of cancer cells may react differently to the same chemical stimuli.”

What the sources say

• ?Not checked — no full text of the sourcecites [198] source
• Partly supported

  Section 2.3 reports that HT1080 cancer cells responded to a chemical gradient, supporting the claim that cancer cells can react to chemical stimuli. It does not show different cancer cell types responding differently to the same stimulus: its comparison with MDA-MB-231 cells concerns interstitial flow, a different cue. (LLM, conf=0.83)

  cites [199] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [200] source
• ?Not checked — no full text of the sourcecites [201] source

In the paper

“They rebuilt largely in vitro 3D tumor tissues and were able to generate a hypoxic environment in the inner core, which greatly recapitulated in vivo spatial oxygen distribution.”

What the sources say

• Partly supported

  The introduction describes oxygen gradients across spheroids that mimic avascular tumors, and the Discussion says limited oxygen diffusion can create a hypoxic core similar to that of solid tumors. The paper does not establish the oxygen distribution in its own HepG2 spheroids, so the claim that these particular structures generated a hypoxic core and closely reproduced the in vivo distribution goes beyond its findings. (LLM, conf=0.82)

  cites [215] sourceExperimental — accuracy not yet measured
• Supported

  The Abstract describes an engineered 3D tumour assembled by rolling a scaffold–tumour strip and says its oxygen gradients and responses are consistent with tumours in vivo. In “Oxygen gradient dynamics reveal HIF-dependent adaptations,” the authors report an outer-to-inner oxygen gradient and severe hypoxia in the deep layers. (LLM, conf=0.94)

  cites [216] source

In the paper

“Current microfluidic tumor models with mimicked vasculature have demonstrated that tumor cells exhibit increased drug resistance when artificial blood vessels were used [81].”

What the sources say

• Partly supported

  The Results (Profiles of Caspase-3 Activity in Different Culture Configurations; page unavailable) report slower and lower maximum drug responses in PC9 lung cancer cells cultured with mimicked microvessels than in static 3D coculture. This supports reduced drug response in that comparison, but the broader claim of increased tumor-cell drug resistance overstates the finding: the authors measured apoptotic response and only speculate that the endothelial layer delayed drug delivery. (LLM, conf=0.84)

  cites [81] 81. Dereli-Korkut, Z., et al., Three dimensional microfluidic cell arrays for ex vivo drug screening with mimicked vascular flow. Analytical Chemistry, 2014. 86(6): p. 2997-3004. sourceExperimental — accuracy not yet measured

In the paper

“Most research is focused on how IFP prompts cancer cells migration and metastasis [157,[167][168][169].”

What the sources say

• ?Could not verify

  The Introduction says interstitial flow can affect cellular behavior and that tumor progression depends on interactions with surrounding cells. It does not say that most research focuses on IFP-induced cancer-cell migration or metastasis. Searches for those topics found no passage making that claim. (LLM, conf=0.74)

  cites [157] sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page unavailable) describes several studies of how IFP and interstitial flow affect cancer-cell migration, and the paper investigates migration and invasion. The Discussion (page unavailable) mentions metastasis only as a potential consequence; it does not establish that most research focuses on migration and metastasis or that IFP prompts metastasis. (LLM, conf=0.83)

  cites [167] sourceExperimental — accuracy not yet measured
• Partly supported

  The introduction (p. 2) says elevated interstitial fluid pressure drives interstitial flow that influences tumor-cell migration. The Discussion (p. 6) links this mechanism to metastasis as a possible implication, but does not demonstrate that it causes metastasis or establish that most research focuses on this question. (LLM, conf=0.84)

  cites [168] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [169] source

In the paper

“Human endothelial cells can sprout in hydrogels to develop a vascular network with dimensions similar to real capillaries [96,107].”

What the sources say

• ?Not checked — no full text of the sourcecites [96] 96. Ahn, J., et al., Probing the effect of bioinspired nanomaterials on angiogenic sprouting using a microengineered vascular system. IEEE Transactions on Nanotechnology, 2017: p. 1-1. source
• ?Could not verify

  The Long Distance Communication section mentions hydrogels as a way to separate cells while allowing signaling proteins to pass between them. The Wound Healing section discusses endothelial-cell migration, but neither section describes human endothelial cells sprouting in hydrogels or forming networks with capillary-like dimensions (searched: sprouting, vascular network, capillaries). (LLM, conf=0.76)

  cites [107] 107. Vu, T.Q., R.M.B. de Castro, and L. Qin, Bridging the gap: microfluidic devices for short and long distance cell-cell communication. Lab on a Chip, 2017. 17(6): p. 1009-1023. 130. Benam, K.H., et al., Engineered in vitro disease models. Annual Review of Pathology: Mechanisms of Disease, 2015. 10: p. 195-262. 131. sourceExperimental — accuracy not yet measured

In the paper

“The uniformly elevated IFP in tumor center is responsible for inhibiting drug delivery [172, 178, 186] while the steep pressure gradients at the periphery favors tumor growth and metastasis[154,[187][188][189][190].”

What the sources say

• ?Not checked — no full text of the sourcecites [172]
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [178]
• Supported

  The paper’s discussion of its model (section labelled Abstract; page not provided) reports elevated IFP in the tumour centre with no transvascular pressure difference. It also states that elevated IFP hinders drug delivery by eliminating the pressure gradients needed for convective penetration. (LLM, conf=0.91)

  cites [186] source

In the paper

“Due to the direct use of tumor tissue, this approach includes many key components in tumor such as heterogeneous cell types and abnormal blood vessel networks.”

What the sources say

• ?Not checked — no full text of the sourcecites [155] source
• Partly supported

  The Introduction (page unavailable) says the biopsy-based approach maintains interactions between tumor tissue and its microenvironment in their biological configuration, and describes tumors as heterogeneous tissue involving multiple cell types. The paper does not say that the cultured biopsies include abnormal blood-vessel networks; its references to vascular capillaries and endothelial cells do not establish that point. (LLM, conf=0.87)

  cites [165] sourceExperimental — accuracy not yet measured

In the paper

“In addition, the various types of cells in tumor tissues were all treated as tumor cells in these studies.”

What the sources say

• ?Not checked — no full text of the sourcecites [155] source
• Partly supported

  The Materials and Methods section (‘Measurement of viability and death’; page unavailable) calculates viability from fluorescence across whole tumor fragments, without describing a separation of cancer cells from other cell types. The Discussion distinguishes cancer cells from stromal components, however, and the paper does not say that every cell type was treated as a tumor cell. The claim is supported as a description of aggregate measurement, but not as a literal classification of all cells. (LLM, conf=0.78)

  cites [165] sourceExperimental — accuracy not yet measured

In the paper

“Although many in vitro microvessel models have been developed, none of them can actually reproduce the architecture of capillaries seen in a tumor [217,218].”

What the sources say

• ?Could not verify

  The Capillaries section describes how tumour-associated capillaries form through intraluminal bridging, but does not compare their architecture with in vitro models. Searches for in vitro microvessel models and their ability to reproduce tumour vessels found no passage addressing the claim. (LLM, conf=0.74)

  cites [217] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [218] source

In the paper

“Even though a tumor is essentially being cultivated in a surrogate human model, this method has demonstrated some success over the years such as the discovery of APC gene suppression which initiates tumor formation in an animal mouse model of human familial adenomatous polyposis [39].”

What the sources say

• ?Not checked — no full text of the sourcecites [39] 39. Fodde, R., et al., A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proceedings of the National Academy of Sciences of the United States of America, 1994. 91(19): p. 8969-8973. source

In the paper

“EMT is initiated when the cells lose adhesion and polarization while acquiring migratory properties as part of its interaction with other cells in a tumor [47].”

What the sources say

• ?Not checked — no full text of the sourcecites [47] 47. Thiery, J.P., et al., Epithelial-Mesenchymal Transitions in Development and Disease. Cell, 2009. 139(5): p. 871-890. source

In the paper

“This can be explained by how the regional differences in a tumor arising from chemical and biological aspects of the niche will result in changes in the physical aspect of the niche.”

In the paper

“Most current reviews either focus on specific fields such as cell migration and 3D cell culture or highlight the biological applications of in vitro tumor models [14][15][16], with limited emphasis on their contribution to anti-cancer drug screening and development.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [14][15][16]

In the paper

“On a macroscopic level, the solid tumor microenvironment is very similar to that of an organ, where it comprises specialized cells being sustained by blood vessels, with each performing a different role in a tumor [17].”

What the sources say

• ?Not checked — no full text of the sourcecites [17] 17. Balkwill, F.R., M. Capasso, and T. Hagemann, The tumor microenvironment at a glance. Journal of Cell Science, 2012. 125(23): p. 5591-5596. source

In the paper

“Moreover, it is important to note that successful translation from animal models to clinical cancer trials only stand at 8% [45].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [45] 45. Mak, I.W.Y., N. Evaniew, and M. Ghert, Lost in translation: animal models and clinical trials in cancer treatment. American Journal of Translational Research, 2014. 6(2): p. 114-118.

In the paper

“For instance, various collagens, including collagen I, II, III, V, and IX, have increased deposition rates during tumor formation [23][24][25].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [23][24][25]

In the paper

“Studies conducted in recent years have demonstrated that the same tumor oncogenes and suppressor genes contribute to the development of cancer in humans and dogs [43].”

What the sources say

• ?Not checked — no full text of the sourcecites [43] 43. Paoloni, M. and C. Khanna, Translation of new cancer treatments from pet dogs to humans. Nat Rev Cancer, 2008. 8(2): p. 147-156. source

In the paper

“There is much value in doing so because the tumor heterogeneity confers unique advantages for the tumor, such as an inherent resistance to therapy [10,11].”

What the sources say

• ?Not checked — no full text of the sourcecites [10] 10. Holohan, C., et al., Cancer drug resistance: An evolving paradigm. Nature Reviews Cancer, 2013. 13(10). source
• ?Not checked — no full text of the sourcecites [11] 11. Trédan, O., et al., Drug resistance and the solid tumor microenvironment. Journal of the National Cancer Institute, 2007. 99(19): p. 1441-1454. source

In the paper

“For instance, leaky blood vessels developed in a tumor will give rise to different sub-populations of cancer cells within a tumor as different hypoxic and pressure differences will be created in the niche (Figure 2).”

In the paper

“This implies that once the tumor explant has been used in an experiment, it may almost be impossible to obtain another explant with the same features to test the repeatability of the results.”

In the paper

“However, in the ECM of a tumor niche, changes in the amount, composition or topography of the ECM can lead to changes in the properties of the ECM itself.”

In the paper

“This increased expression of HIF-1 has also been demonstrated to drive angiogenesis by promoting the formation of vessels in the tumor microenvironment through the upregulation of the vascular endothelial growth factor (VEGF) protein [28].”

What the sources say

• ?Not checked — no full text of the sourcecites [28] 28. Lin, C., et al., Hypoxia induces HIF-1Œ± and VEGF expression in chondrosarcoma cells and chondrocytes. Journal of Orthopaedic Research, 2004. 22(6): p. 1175-1181. source

In the paper

“As compared to the traditional transwell method, the monolayer design also has the added advantage of easily generating shear stress.”

What the sources say

• ?Not checked — no full text of the sourcecites [106] 106. Ferrara, N. and R.S. Kerbel, Angiogenesis as a therapeutic target. Nature, 2005. 438(7070): p. 967-974. 122. Reymond, N., B.B. d'Agua, and A.J. Ridley, Crossing the endothelial barrier during metastasis. Nature Reviews Cancer, 2013. 13(12): p. 858-870. 123. Orimo, A., et al., Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 2005. 121(3): p. 335-348. 124. Polanska, U.M. and A. Orimo, Carcinoma-associated fibroblasts: Non-neoplastic tumour-promoting mesenchymal cells. Journal of cellular phys source

In the paper

“In this study, the migration speed of cancer cells in the ECM was shown to be slower than that in ECM/vessel interface and predefined matrix tracks.”

What the sources say

• ?Not checked — no full text of the sourcecites [88] 88. Wong, A.D. and P.C. Searson, Live-cell imaging of invasion and intravasation in an artificial microvessel platform. Cancer research, 2014. 74(17): p. 4937-45. source

In the paper

“Endothelial cells monolayer is the most direct approach to mimic blood vessel function in a microfluidic chip.”

In the paper

“Many different material coatings, such as agarose, poly-HEMA and pluronic acid coatings have been proved to work well in forming viable cellular spheroids [67][68][69][70].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [67][68][69][70]

In the paper

“Without recruiting new blood vessels, the size of a tumor is limited to a few millimeters in diameter [104].”

What the sources say

• ?Not checked — no full text of the sourcecites [104] 104. Abadeer, N.S. and C.J. Murphy, Recent progress in cancer thermal therapy using gold nanoparticles. The Journal of Physical Chemistry C, 2016. 120(9): p. 4691-4716. 114. Liu, P.-F., et al., Far from resolved: Stromal cell-based iTRAQ research of muscle-invasive bladder cancer regarding heterogeneity. Oncology reports, 2014. 32(4): p. 1489-1496. 115. De Palma, M. and C.E. Lewis, Macrophage regulation of tumor responses to anticancer therapies. Cancer cell, 2013. 23(3): p. 277-286. 116. Hida, K., et al., Tumour endothelial cells acquire drug resistance in a tumour microenvironment. Journal o source

In the paper

“In contrast, a microfluidic tumor-on-a-chip can mimic the human body environment without the presence of foreign environmental factors.”

In the paper

“However, these models cannot predict tumor cell response accurately due to lack of a physiologically relevant microenvironment.”

In the paper

“Hence, there is a need for 3D models in order to obtain more information such as drug penetration or to aid in understanding the tumor niche better.”

In the paper

“This may be attributed to how 2D layers are still spatially irrelevant given that actual tumors are 3D in nature.”

In the paper

“By implanting three such vessels in one chip and culturing HCCLM9 cancer cells in between, it was shown that the endothelial monolayer and pulse flow could significantly delay tumor migration [86].”

What the sources say

• ?Not checked — no full text of the sourcecites [86] 86. Wang, X.-Y., et al., An artificial blood vessel implanted three-dimensional microsystem for modeling transvascular migration of tumor cells. Lab on a Chip, 2015. 15(4): p. 1178-1187. source

In the paper

“However, the main advantage is that the 2D co-culture model offers a quick and simple method to mimic specific aspects of the tumor microenvironment.”

In the paper

“Vasculature plays an essential role in the growth and metastasis of malignant tumors [103].”

What the sources say

• ?Not checked — no full text of the sourcecites [103] 103. Sun, T., et al., Engineered nanoparticles for drug delivery in cancer therapy. Angewandte Chemie International Edition, 2014. 53(46): p. 12320-12364. 113. source

In the paper

“Shear stress helps cells arrange themselves to establish the barrier function [106].”

What the sources say

• ?Not checked — no full text of the sourcecites [106] 106. Ferrara, N. and R.S. Kerbel, Angiogenesis as a therapeutic target. Nature, 2005. 438(7070): p. 967-974. 122. Reymond, N., B.B. d'Agua, and A.J. Ridley, Crossing the endothelial barrier during metastasis. Nature Reviews Cancer, 2013. 13(12): p. 858-870. 123. Orimo, A., et al., Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 2005. 121(3): p. 335-348. 124. Polanska, U.M. and A. Orimo, Carcinoma-associated fibroblasts: Non-neoplastic tumour-promoting mesenchymal cells. Journal of cellular phys source

In the paper

“The level of complexity increases as one progress from the use of endothelial cells monolayer to circular endothelial cells tube and to the functional vascular network.”

In the paper

“Different from the previous two types of devices where the artificial blood vessel is formed on a well-defined surface, some devices prompt endothelial cells to sprout in the hydrogel to develop an irregular vascular network to mimic in vivo capillary vessel networks (Figure 3c).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [94][95][96][97]107]

In the paper

“However, the main drawback is that it is not able to mimic certain cell-cell interactions which cannot be transmitted through culture media such as the ECM interaction generated by fibroblasts and the immune response from WBCs.”

In the paper

“Different from normal fibroblasts, cancer-associated fibroblasts proliferate faster, produce more extracellular matrix and secrete unique cytokine, which significantly enhances carcinogenesis [123, 124].”

What the sources say

• ?Not checked — no full text of the sourcecites [123] 123. Somaweera, H., A. Ibraguimov, and D. Pappas, A review of chemical gradient systems for cell analysis. Anal Chim Acta, 2016. 907: p. 7-17. 194. source
• ?Not checked — no full text of the sourcecites [124] 124. Brennan, M.D., et al., Oxygen control with microfluidics. Lab Chip, 2014. 14(22): p. 4305-18. 195. Eccles, S.A., Targeting key steps in metastatic tumour progression. Current opinion in genetics & development, 2005. 15(1): p. 77-86. 196. source

In the paper

“This is, however, still different from the actual situation in the human body where shear stresses also exist inside the tumor [161].”

What the sources say

• ?Not checked — no full text of the sourcecites [161] source

In the paper

“Therefore, mimicking cell-cell interactions is very necessary for the design of a comprehensive in vitro tumor model.”

In the paper

“In addition, this shear stress can also prompt vascular angiogenesis against the direction of interstitial flow [152].”

What the sources say

• ?Not checked — no full text of the sourcecites [152] source

In the paper

“As compared to a mixed co-culture, a separate co-culture can easily distinguish the different cell types cultured in the device without fluorescent staining.”

In the paper

“Although this shear stress is very small when compared with the intravascular shear stress, it can still stimulate some oncogenic signaling pathways on cancer cells [150] as well as upregulate TGFβ and activate fibroblast contraction to stiffen the ECM [151].”

What the sources say

• ?Not checked — no full text of the sourcecites [150] source

In the paper

“Its interplay with malignant cells is also key to cancer metastasis [122].”

What the sources say

• ?Not checked — no full text of the sourcecites [122] 122. Diresta, G.R., et al., Cell proliferation of cultured human cancer cells are affected by the elevated tumor pressures that exist in vivo. Annals of biomedical engineering, 2005. 33(9): p. 1270-80. 190. Nathan, S.S., et al., Elevated Physiologic Tumor Pressure Promotes Proliferation and Chemosensitivity in Human Osteosarcoma. Clinical Cancer Research, 2005. 11(6): p. 2389. 191. Montel, F., et al., Isotropic stress reduces cell proliferation in tumor spheroids. New Journal of Physics, 2012. 14(5): p. 055008. 192. Tse, J.M., et al., Mechanical compression drives cancer cells toward invasive source

In the paper

“Elevated extracellular stresses have been observed in many tumors[170][171][172][173][174][175][176][177][178].”

What the sources say

• ?Not checked — no full text of the sourcecites [170] source
• ?Not checked — no full text of the sourcecites [171] source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [172]
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [173]
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [174]
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [175]
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [176]
• ?Not checked — no full text of the sourcecites [177] source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [178]

In the paper

“Chemical gradients play an important role in tumor cell invasion of metastatic cancer [195,196] as it significantly directs the migration and differentiation of tumor cells.”

What the sources say

• ?Not checked — no full text of the sourcecites [195] source
• ?Not checked — no full text of the sourcecites [196] source

In the paper

“As such, it is hard to identify the effect of IFP on tumor alone.”

In the paper

“Although many current microfluidic devices have conducted research on the effect of IFP on tumor cells, they inadvertently mixed up an elevated IFP with fluid shear stress when a pressure-driven fluid flow is used (Figure 4c).”

In the paper

“Current microfluidic devices are capable of recapitulating in vivo chemical and oxygen gradient independently.”

In the paper

“However, the artificial microenvironment in a microfluidic chip is still a long way from the human body in terms of blood vessel architecture, cell lines used in co-culture models and functionality of mimicked elements.”

In the paper

“However, they are not able to generate oxygen gradient with spatial controls.”

In the paper

“Fully recapitulated tumor microenvironment in vitro is also impossible with current technologies.”

In the paper

“However, due to the impairment of blood and lymph vessels in a tumor, the IFP could rise up to more than 30mmHg at the center and drop drastically to the normal value at the periphery of a tumor[185].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [185]

In the paper

“As compared to SS, the impact of interstitial pressure on tumors is better studied using microfluidics.”

In the paper

“All the present approaches that mimic IFP have an associated shear stress due to the presence of significant fluid flow.”

In the paper

“Spatial control of oxygen concentration, which allows for the study of cancer cells respond to different oxygen levels, is important for it can reproduce oxygen distribution seen in actual tumors.”

In the paper

“Cell sources used in most in vitro tumor models described are cell lines derived from human patients.”

In the paper

“Besides, the current gold standard to validate proposed models still involves comparing the result with animal tests.”

In the paper

“For example, the efficacy of some anticancer drugs can be overestimated when these drugs are able to kill non-tumor cells in the tumor tissue because the drug efficacy is assessed based on the general cell viability of the whole tumor.”

In the paper

“This is due to the difficulties in culturing primary tumor cells harvested from liquid biopsy or solid tumors and the heterogeneity in utilizing clinical samples.”

In the paper

“This can be misleading in predicting tumor response in vitro.”

In the paper

“Some microfluidic works have already demonstrated the feasibility of conducting patients' cell culture in microfluidic devices [133][134][135]163].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [133][134][135]163]

In the paper

“However, the relevance of using immortalized cells for biological studies is questionable with issues of mutation and contamination [219,220].”

What the sources say

• ?Not checked — no full text of the sourcecites [219] source
• ?Not checked — no full text of the sourcecites [220] source