Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2008

Open Access 01-12-2008 | Research article

Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours

Authors: Sarah Jane Lunt, Tuula MK Kalliomaki, Allison Brown, Victor X Yang, Michael Milosevic, Richard P Hill

Published in: BMC Cancer | Issue 1/2008

Login to get access

Abstract

Background

High tumour interstitial fluid pressure (IFP) has been adversely linked to poor drug uptake in patients, and to treatment response following radiotherapy in cervix cancer patients. In this study we measured IFP values in a selection of murine and xenograft models, spontaneously arising or transplanted either intramuscularly (i/m) or orthotopically and analysed their relationship to tumour vascularity and metastatic spread.

Methods

KHT-C murine fibrosarcoma, ME180 and SiHa human cervix carcinoma were grown either intramuscularly (i/m), sub-cutaneously (s/c) or orthotopically. Polyoma middle-T (MMTV-PyMT) transgenic spontaneous mammary tumours were studied either as spontaneous tumours or following orthotopic or i/m transplantation. IFP was measured in all tumours using the wick-in-needle method. Spontaneous metastasis formation in the lungs or lymph nodes was assessed in all models. An immunohistochemical analysis of tumour hypoxia, vascular density, lymphatic vascular density and proliferation was carried out in ME180 tumours grown both i/m and orthotopically. Blood flow was also assessed in the ME180 model using high-frequency micro-ultrasound functional imaging.

Results

Tumour IFP was heterogeneous in all the models irrespective of growth site: KHT-C i/m: 2–42 mmHg, s/c: 1–14 mmHg, ME180: i/m 5–68 mmHg, cervix 4–21 mmHg, SiHa: i/m 20–56 mmHg, cervix 2–26 mmHg, MMTV-PyMT: i/m: 13–45 mmHg, spontaneous 2–20 mmHg and transplanted 2–22 mmHg. Additionally, there was significant variation between individual tumours growing in the same mouse, and there was no correlation between donor and recipient tumour IFP values. Metastatic dissemination to the lungs or lymph nodes demonstrated no correlation with tumour IFP. Tumour hypoxia, proliferation, and lymphatic or blood vessel density also showed no relationship with tumour IFP. Speckle variance analysis of ultrasound images showed no differences in vascular perfusion between ME180 tumours grown i/m versus orthotopically despite differences in IFP.

Conclusion

Our studies across a range of different tumour models showed substantial heterogeneity in tumour IFP, suggesting differences in the vascular development and interstitial fluid dynamics in the individual tumours. The results demonstrate a strong stochastic aspect to tumour IFP development, notably the variation apparent between different tumours within the same animal and the lack of correlation between donor and recipient tumours.
Appendix
Available only for authorised users
Literature
1.
Jain RK: Transport of molecules in the tumor interstitium: a review. Cancer Res. 1987, 47: 3039-3051.PubMed
2.
Jain RK: Transport of molecules across tumor vasculature. Cancer Metastasis Rev. 1987, 6 (4): 559-593. 10.1007/BF00047468.CrossRefPubMed
3.
Heldin CH, Rubin K, Pietras K, Ostman A: High interstitial fluid pressure - an obstacle in cancer therapy. Nat Rev Cancer. 2004, 4 (10): 806-813. 10.1038/nrc1456.CrossRefPubMed
4.
Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM: Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol. 2003, 163 (5): 1801-1815.CrossRefPubMedPubMedCentral
5.
Baxter LT, Jain RK: Transport of fluid and macromolecules in tumors I. Role of interstitial pressure and convection. Microvasc Res. 1989, 37: 77-104. 10.1016/0026-2862(89)90074-5.CrossRefPubMed
6.
Milosevic M, Fyles A, Hedley D, Hill R: The human tumor microenvironment: invasive (needle) measurement of oxygen and interstitial fluid pressure. Semin Radiat Oncol. 2004, 14 (3): 249-258. 10.1016/j.semradonc.2004.04.006.CrossRefPubMed
7.
Milosevic M, Fyles A, Hedley D, Pintilie M, Levin W, Manchul L, Hill R: Interstitial fluid pressure predicts survival in patients with cervix cancer independent of clinical prognostic factors and tumor oxygen measurements. Cancer Res. 2001, 61 (17): 6400-6405.PubMed
8.
Jain RK: Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005, 307 (5706): 58-62. 10.1126/science.1104819.CrossRefPubMed
9.
Fyles A, Milosevic M, Pintilie M, Syed A, Levin W, Manchul L, Hill RP: Long-term performance of interstial fluid pressure and hypoxia as prognostic factors in cervix cancer. Radiother Oncol. 2006, 80 (2): 132-137. 10.1016/j.radonc.2006.07.014.CrossRefPubMed
10.
Eikenes L, Bruland OS, Brekken C, Davies Cde L: Collagenase increases the transcapillary pressure gradient and improves the uptake and distribution of monoclonal antibodies in human osteosarcoma xenografts. Cancer Res. 2004, 64 (14): 4768-4773. 10.1158/0008-5472.CAN-03-1472.CrossRefPubMed
11.
Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, Rubin K: Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res. 2001, 61 (7): 2929-2934.PubMed
12.
Pietras K, Stumm M, Hubert M, Buchdunger E, Rubin K, Heldin CH, McSheehy P, Wartmann M, Ostman A: STI571 enhances the therapeutic index of epothilone B by a tumor-selective increase of drug uptake. Clin Cancer Res. 2003, 9 (10 Pt 1): 3779-3787.PubMed
13.
Pietras K, Rubin K, Sjoblom T, Buchdunger E, Sjoquist M, Heldin CH, Ostman A: Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res. 2002, 62 (19): 5476-5484.PubMed
14.
Rubin K, Sjoquist M, Gustafsson AM, Isaksson B, Salvessen G, Reed RK: Lowering of tumoral interstitial fluid pressure by prostaglandin E(1) is paralleled by an increased uptake of (51)Cr-EDTA. Int J Cancer. 2000, 86 (5): 636-643. 10.1002/(SICI)1097-0215(20000601)86:5<636::AID-IJC6>3.0.CO;2-R.CrossRefPubMed
15.
Salnikov AV, Iversen VV, Koisti M, Sundberg C, Johansson L, Stuhr LB, Sjoquist M, Ahlstrom H, Reed RK, Rubin K: Lowering of tumor interstitial fluid pressure specifically augments efficacy of chemotherapy. Faseb J. 2003, 17 (12): 1756-8. Epub 2003 Jul 18..PubMed
16.
Netti PA, Baxter LT, Boucher Y, Skalak R, Jain RK: Time-dependent behaviour of interstitial fluid pressure in solid tumors: implications for drug delivery. Cancer Res. 1995, 55: 5451-5458.PubMed
17.
Netti PA, Hamberg LM, Babich JW, Kierstead D, Graham W, Hunter GJ, Wolf GL, Fischman A, Boucher Y, Jain RK: Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules. Proc Natl Acad Sci U S A. 1999, 96 (6): 3137-3142. 10.1073/pnas.96.6.3137.CrossRefPubMedPubMedCentral
18.
Roh HD, Kalnicki S, Buchsbaum R, Bloomer WD, Jain RK: Interstitial hypertension in carcinoma of uterine cervix in patients: Possible correlation with tumor oxygenation and radiation response. Cancer Res. 1991, 51: 6695-6698.PubMed
19.
Curti BD, Urba WJ, Alvord WG, Janik JE, Smith JW, Madara K, Longo DL: Interstitial pressure of subcutaneous nodules in melanoma and lymphoma patients: changes during treatment. Cancer Res. 1993, 53: 2204-2207.PubMed
20.
Rofstad EK, Tunheim SH, Mathiesen B, Graff BA, Halsor EF, Nilsen K, Galappathi K: Pulmonary and lymph node metastasis is associated with primary tumor interstitial fluid pressure in human melanoma xenografts. Cancer Res. 2002, 62 (3): 661-664.PubMed
21.
Less JR, Posner MC, Boucher Y, Borochovitz D, Wolmark N, Jain RK: Interstitial hypertension in human breast and colorectal tumors. Cancer Res. 1992, 52: 6371-6374.PubMed
22.
Taghian AG, Abi-Raad R, Assaad SI, Casty A, Ancukiewicz M, Yeh E, Molokhia P, Attia K, Sullivan T, Kuter I, Boucher Y, Powell SN: Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications. J Clin Oncol. 2005, 23 (9): 1951-1961. 10.1200/JCO.2005.08.119.CrossRefPubMed
23.
Nathanson SD, Nelson L: Interstitial fluid pressure in breast cancer, benign breast conditions, and breast parenchyma. Ann Surg Oncol. 1994, 1: 333-338.CrossRefPubMed
24.
Boucher Y, Kirkwood JM, Opacic D: Interstitial hypertension in superficial metastatic melanomas in humans. Cancer Res. 1991, 51: 6691-6694.PubMed
25.
DiResta GR, Lee J, Larson SM, Arbit E: Characterization of neuroblastoma xenograft in rat flank. I. Growth, interstitial fluid pressure, and interstitial fluid velocity distribution profiles. Microvasc Res. 1993, 46 (2): 158-177. 10.1006/mvre.1993.1044.CrossRefPubMed
26.
Boucher Y, Lee I, Jain RK: Lack of general correlation between interstitial fluid pressure and oxygen partial pressure in solid tumors. Microvasc Res. 1995, 50 (2): 175-182. 10.1006/mvre.1995.1051.CrossRefPubMed
27.
Hori K, Suzuki M, Saito S, Tanda S, Zhang QH, Li HC: Changes in vessel pressure and interstitial fluid pressure of normal subcutis and subcutaneous tumor in rats due to angiotensin II. Microvasc Res. 1994, 48 (2): 246-256. 10.1006/mvre.1994.1052.CrossRefPubMed
28.
Znati CA, Rosenstein M, Boucher Y, Epperly MW, Bloomer WD, Jain RK: Effect of radiation on interstitial fluid pressure and oxygenation in a human tumor xenograft. Cancer Res. 1996, 56 (5): 964-968.PubMed
29.
Kerbel RS, Cornil I, Theodorescu D: Importance of orthotopic transplantation procedures in assessing the effects of transfected genes on human tumor growth and metastasis. Cancer Metastasis Rev. 1991, 10 (3): 201-215. 10.1007/BF00050792.CrossRefPubMed
30.
Brekken C, Bruland OS, de Lange Davies C: Interstitial fluid pressure in human osteosarcoma xenografts: significance of implantation site and the response to intratumoral injection of hyaluronidase. Anticancer Res. 2000, 20 (5B): 3503-3512.PubMed
31.
Cairns RA, Hill RP: Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma. Cancer Res. 2004, 64 (6): 2054-2061. 10.1158/0008-5472.CAN-03-3196.CrossRefPubMed
32.
Cairns RA, Kalliomaki T, Hill RP: Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. Cancer Res. 2001, 61 (24): 8903-8908.PubMed
33.
Guy CT, Cardiff RD, Muller WJ: Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol. 1992, 12 (3): 954-961.CrossRefPubMedPubMedCentral
34.
Hagendoorn J, Tong R, Fukumura D, Lin Q, Lobo J, Padera TP, Xu L, Kucherlapati R, Jain RK: Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis. Cancer Res. 2006, 66 (7): 3360-3364. 10.1158/0008-5472.CAN-05-2655.CrossRefPubMed
35.
Bristow RG, Hardy PA, Hill RP: Comparison between in vitro radiosensitivity and in vivo radioresponse of murine tumor cell lines. I: Parameters of in vitro radiosensitivity and endogenous cellular glutathione levels. Int J Radiat Oncol Biol Phys. 1990, 18 (1): 133-145.CrossRefPubMed
36.
Cairns RA, Hill RP: A fluorescent orthotopic model of metastatic cervical carcinoma. Clin Exp Metastasis. 2004, 21 (3): 275-281. 10.1023/B:CLIN.0000037729.75981.9e.CrossRefPubMed
37.
Young SD, Marshall RS, Hill RP: Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc Natl Acad Sci U S A. 1988, 85 (24): 9533-9537. 10.1073/pnas.85.24.9533.CrossRefPubMedPubMedCentral
38.
Fadnes HO, Reed RK, Aukland K: Interstitial fluid pressure in rats measured with a modified wick technique. Microvasc Res. 1977, 14 (1): 27-36. 10.1016/0026-2862(77)90138-8.CrossRefPubMed
39.
Skliarenko JV, Lunt SJ, Gordon ML, Vitkin A, Milosevic M, Hill RP: Effects of the vascular disrupting agent ZD6126 on interstitial fluid pressure and cell survival in tumors. Cancer Res. 2006, 66 (4): 2074-2080. 10.1158/0008-5472.CAN-05-2046.CrossRefPubMed
40.
Franco M, Man S, Chen L, Emmenegger U, Shaked Y, Cheung AM, Brown AS, Hicklin DJ, Foster FS, Kerbel RS: Targeted anti-vascular endothelial growth factor receptor-2 therapy leads to short-term and long-term impairment of vascular function and increase in tumor hypoxia. Cancer Res. 2006, 66 (7): 3639-3648. 10.1158/0008-5472.CAN-05-3295.CrossRefPubMed
41.
Yang VXD, Needles A, Vray D, et al: High frequency ultrasound speckle flow imaging: comparison with doppler optical coherence tomography (DOCT). Proc IEEE Ultrasound Symp. 2004, 1: 453-456.
42.
Gutmann R, Leunig M, Feyh J, Goetz AE, Messmer K, Kastenbauer E, Jain RK: Interstitial hypertension in head and neck tumors in patients: correlation with tumor size. Cancer Res. 1992, 52: 1993-1995.PubMed
43.
Podobnik B, Sersa G, Miklavcic D: Effect of hydralazine on interstitial fluid pressure in experimental tumours and in normal tissue. In Vivo. 2001, 15 (5): 417-424.PubMed
44.
Tufto I, Rofstad EK: Interstitial fluid pressure and capillary diameter distribution in human melanoma xenografts. Microvasc Res. 1999, 58 (3): 205-214. 10.1006/mvre.1999.2184.CrossRefPubMed
45.
Tufto I, Rofstad EK: Interstitial fluid pressure in human melanoma xenografts. Relationship to fractional tumor water content, tumor size, and tumor volume-doubling time. Acta Oncol. 1995, 34 (3): 361-365. 10.3109/02841869509093990.CrossRefPubMed
46.
Rofstad EK, Mathiesen B, Henriksen K, Kindem K, Galappathi K: The tumor bed effect: increased metastatic dissemination from hypoxia-induced up-regulation of metastasis-promoting gene products. Cancer Res. 2005, 65 (6): 2387-2396. 10.1158/0008-5472.CAN-04-3039.CrossRefPubMed
47.
De Jaeger K, Kavanagh MC, Hill RP: Relationship of hypoxia to metastatic ability in rodent tumours. Br J Cancer. 2001, 84 (9): 1280-1285. 10.1054/bjoc.2001.1743.CrossRefPubMed
48.
Rofstad EK, Danielsen T: Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis. Br J Cancer. 1999, 80 (11): 1697-1707. 10.1038/sj.bjc.6690586.CrossRefPubMedPubMedCentral
49.
Rofstad EK, Sundfor K, Lyng H, Trope CG: Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis. Br J Cancer. 2000, 83 (3): 354-359. 10.1054/bjoc.2000.1266.CrossRefPubMedPubMedCentral
50.
Rofstad EK, Halsor EF: Hypoxia-associated spontaneous pulmonary metastasis in human melanoma xenografts: involvement of microvascular hot spots induced in hypoxic foci by interleukin 8. Br J Cancer. 2002, 86 (2): 301-308. 10.1038/sj.bjc.6600052.CrossRefPubMedPubMedCentral
51.
Diresta GR, Nathan SS, Manoso MW, Casas-Ganem J, Wyatt C, Kubo T, Boland PJ, Athanasian EA, Miodownik J, Gorlick R, Healey JH: Cell proliferation of cultured human cancer cells are affected by the elevated tumor pressures that exist in vivo. Ann Biomed Eng. 2005, 33 (9): 1270-1280. 10.1007/s10439-005-5732-9.CrossRefPubMed
52.
Nathan SS, DiResta GR, Casas-Ganem JE, Hoang BH, Sowers R, Yang R, Huvos AG, Gorlick R, Healey JH: Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma. Clin Cancer Res. 2005, 11 (6): 2389-2397. 10.1158/1078-0432.CCR-04-2048.CrossRefPubMed
53.
Baxter LT, Jain RK, Svensjo E: Vascular permeability and interstitial diffusion of macromolecules in the hamster cheek pouch: effects of vasoactive drugs. Microvasc Res. 1987, 34 (3): 336-348. 10.1016/0026-2862(87)90066-5.CrossRefPubMed
54.
Jain RK, Tong RT, Munn LL: Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res. 2007, 67 (6): 2729-2735. 10.1158/0008-5472.CAN-06-4102.CrossRefPubMedPubMedCentral
55.
Boucher Y, Baxter LT, Jain RK: Interstitial pressure gradients in tissue isolated and subcutaneous tissues: implications for therapy. Cancer Res. 1990, 50: 4478-4484.PubMed
56.
Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK: Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004, 64 (11): 3731-3736. 10.1158/0008-5472.CAN-04-0074.CrossRefPubMed
57.
Tufto I, Lyng H, Rofstad EK: Interstitial fluid pressure, perfusion rate and oxygen tension in human melanoma xenografts. Br J Cancer Suppl. 1996, 27 (): S252-S255.PubMedPubMedCentral
Metadata
Title
Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours
Authors
Sarah Jane Lunt
Tuula MK Kalliomaki
Allison Brown
Victor X Yang
Michael Milosevic
Richard P Hill
Publication date
01-12-2008
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2008
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-8-2

Other articles of this Issue 1/2008

BMC Cancer 1/2008 Go to the issue

Research article

Breast cancer, psychological distress and life events among young women

Research article

Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells

Research article

Tight correlation between expression of the Forkhead transcription factor FOXM1 and HER2 in human breast cancer

Research article

Incidence, mortality and survival patterns of prostate cancer among residents in Singapore from 1968 to 2002

Research article

Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

Research article

Immunological tolerance and tumor rejection in embryo-aggregated chimeric mice – Lessons for tumor immunity
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits