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Menebar Ilmu Pengetahuan

Tumor vasculature

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Pembuluh darah tumor bukanlah jalur suplai nutrisi yang sederhana ke tumor. Perannya meregulasi patofisiologi tumor padat dari pertumbuhan tumor, invasi, metastasis, dan respon terhadap berbagai terapi. Terdapat perbedaan mikrovesel pada kondisi normal dan tumor: microvessel yang normal terdiri dari arteriol, kapiler, cand venula, dan bentuknya terorganisasi dengan baik, teratur, dan fungsional arsitektur. Sedangkan tumor vessels dilated, saccular, tortuous, dan heterogeneous in their spatial distribution. Pembuluh darah normal ditandai dengan dikotomis percabangan, tetapi pembuluh darah tumor yang terorganisir dan memiliki trifurcations dan cabang dengan diameter rata.

Vessel wall structure is also abnormal in tumors. Large inter-endothelial junctions, increased numbers of fenestrations, vesicles, and vesicovacuolar channels, and a lack of normal basement membrane are often found in tumor vessels. Perivascular cells have abnormal morphology and heterogeneous association with tumor vessels.

2. Parameter biokimia

Hipoksia dan asidosis adalah hallmark dari metabolisme abnormal tumor padat.

– hipoksia.

1. Menyebabkan gagalnya radiasi karena menjadi tidak sensitif.

2. Tumor hypoxia is also associated with resistance to some chemotherapeutics such as bleomycin and neocarzinostatin

– asidosis. Asidosis bisa terjadi karena penimbunan asam laktat.

1. Kondisi asam menghambat uptake obat-obat basa seperti doksorubisin dan mitoksantron.

2. Immune cells targeting tumor cells are not fully functional under hypoxic and/or acidic conditions and thus allow tumors to evade the host immune response and cell based therapies.

3. Both hypoxia and acidic pH can induce expression of angiogenic factors and thus, contribute to growth and metastasis of tumors

Referensi

Fukumura D, Jain RK. Tumor microvasculature and microenvironment : Targets for anti-angiogenesis and normalization. Microvascular Research. 2007;74:72 – 84.

Continued … (part 2)

Kondisi hipoksia (kekurangan oksigen) dan asidosis (pH rendah) adalah hallmark dari agresivitas kanker pada lingkungan mikro tumor (tumor microenvironment).

  1. Cancer cells utilise glycolysis for energy production, even in oxygenated conditions this is known as the ‘Warburg effect’. The molecular mechanisms underpinning the Warburg effect are poorly understood
  2. Cellular hypoxia is usually considered to be 0.5–1% (7 mmHg) of oxygen [8].
  3. The lack of oxygen in a tumor is primarily due to the enlargement of oxygen diffusion distances, partially because of less ordered vasculature unable to deliver enough oxygen.
  4. Tumor areas may also undergo transient changes of oxygen levels or chronic hypoxia after the generation of malformed leaky tumor vessels [9].
  5. The molecular basis for the ability of cancer cells to migrate, invade and metastasize in hypoxic conditions is still unclear, although some important molecules have been elucidated.
  6. The major regulator of hypoxic response is hypoxia-inducible factor-1 (HIF-1a), which accumulates under low oxygen level and acts as a transcription factor for over 100 target genes [7,10].
  7. Hypoxia triggers epithelial–mesenchymal transition (EMT) which is a factor that facilitates cell migration [38,39].
  8. The hypoxic state of tumors is not always chronic, but for some areas it changes on time [12,51]. Fluctuating hypoxia, i.e. alternating hypoxia and reoxygenation, has been speculated to be involved in tumor stem cell maintenance [52].
  9. The main consequence of tumor hypoxia, and the cause for many of the cellular responses, is the stabilization and activation of HIF-1a [57].
  10. Hypoxia upregulates various angiogenic growth factors, including VEGF, Ang2, PDGF, placenta growth factor (PlGF), transforming growth factor (TGF), IL-8, and hepatocyte growth factor (HGF) [Harris, 2002]. Of the various molecules involved in sensing and responding to hypoxia, Hypoxia inducible factor-1a (HIF-1a) is considered to be the master regulator of oxygen homeostasis [Semenza, 2003].
  11. Low extracellular pH causes stress-induced alteration of gene expression, including the upregulation of VEGF and IL-8 in tumor cells in vitro [Xu et al., 2002].
  12. Oxygen is an important component of radiation therapy [Brown, 1999]. Ionized radiation directly and indirectly damages DNA, and the effect of both is dependent on oxygen. Therefore, hypoxia in solid tumors significantly reduces their radiation sensitivity.
  13. Tumor hypoxia is also associated with resistance to some chemotherapeutics such as bleomycin and neocarzinostatin [Brown, 1999].
  14. Hypoxia induces apoptosis via p53 and HIF-1-dependent mechanisms [Carmeliet et al., 1998]. On the other hand, tumor cells develop many mechanisms to survive under hypoxic conditions including HIF-HRE mediated inductions of the genes for angiogenesis, vasodilation, glycolysis, and hematopoiesis [Harris, 2002]. Mutations in p53 make tumor cells resistant to apoptosis and more prone to further mutations. The balance between hypoxia-induced apoptosis/necrosis and the increased resistance to cell death mediated by various hypoxia-induced pathways determines whether a tumor can survive and even grow under hypoxic conditions.
  15. Immune cells targeting tumor cells cannot be fully functional under hypoxic conditions and thus, allow tumors to evade the host immune response and cell based therapies.

Asidosis

  1. Another consequence of the abnormal microcirculation of the tumor is low extracellular pH. There are at least two sources of H+ ions in tumors—lactic acid and carbonic acid [Helm- linger et al., 2002; Pouyssegur et al., 2006]. The former results from anaerobic glycolysis and the latter from conversion of CO2 and H2O via carbonic anhydrase.
  2. The intracellular pH of cancer cells remains neutral or alkaline (pH 7.4), however, in spite of the acidic extracellular pH.
  3. Despite the low extracellular pH, the intracellular pH in tumor cells in vivo remains neutral. As a consequence, significant intracellular–extracellular pH difference exists in tumors.
  4. This trans-membrane pH gradient hinders the cellular uptake of weak base drugs such as adriamycin, doxorubicin, and mitoxantrone and thus, their efficacy [Vukovic and Tannock, 1997].
  5. Acidic pH also causes dysfunction of immune cells.
  6. One would expect low extracellular pH and hypoxia to track each other and to co-localize with regions of low blood flow. Surprisingly, there is alackof spatial correlationamongthese parameters (Fig. 3), a discovery made possible by recent developments in optical techniques that permit the simultaneous high-resolution mapping of multiple physiological parameters [Helmlinger et al., 1997]. A potential explanation for this lack of concordance is that some perfused tumor vessels carry hypoxic blood [Helmlinger et al., 1997]. Thus, although they might not be able to deliver adequate oxygen to the surrounding cells, they may be able to carry away the waste products (e.g., lactic acid).

Source:

Fukumura D, Jain RK. Tumor microvasculature and microenvironment : Targets for anti-angiogenesis and normalization. Microvascular Research. 2007;74:72 – 84.

Teppo S, Sundquist E, Vered M, et al. The hypoxic tumor microenvironment regulates invasion of aggressive oral carcinoma cells. Experimental Cell Research. 2013;319(4):376-389. Available at: http://dx.doi.org/10.1016/j.yexcr.2012.12.010.

Referensi

[8] L.B. Gardner, P.G. Corn, Hypoxic regulation of mRNA expression, Cell Cycle (2008) 1916–1924.

[9] P. Carmeliet, Angiogenesis in life, disease and medicine, Nature 438 (2005) 932–936.

[7] E.B. Rankin, A.J. Giaccia, The role of hypoxia-inducible factors in tumorigenesis, Cell Death Differ. 15 (2008) 678–685.

[10] R.H. Wenger, D.P. Stiehl, G. Camenisch, Integration of oxygen signaling at the consensus HRE, Sci. STKE (306) re12.

[38] V.H. Haase, Oxygen regulates epithelial-to-mesenchymal tran- sition: insights into molecular mechanisms and relevance to disease, Kidney Int. 76 (2009) 492–499.

[39] M. Jiao, K.J. Nan, Activation of PI3 kinase/Akt/HIF-1a pathway contributes to hypoxia-induced epithelial-mesenchymal transition and chemoresistance in hepatocellular carcinoma, Int. J. Oncol. 40 (2012) 461–468.

[12] H.L. Janssen, K.M. Haustermans, A.J. Balm, A.C. Begg, Hypoxia in head and neck cancer: how much, how important?, Head Neck 27 (2005) 622–638.

[51] M.W. Dewhirst, Concepts of oxygen transport at the microcirculatory level, Semin. Radiat. Oncol. 8 (1998) 143–150.

[52] Q. Sun, X. Li, X. Lu, B. Di, Cancer stem cells may be mostly maintained by fluctuating hypoxia, Med. Hypotheses 76 (2011) 471–473.

[57] G.L. Wang, G.L. Semenza, Purification and characterization of hypoxia-inducible factor 1, J. Biol. Chem. 270 (1995) 1230–1237.

Harris AL. 2002. Hypoxia: A key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47.

Semenza GL. 2003. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732.

Xu L, Fukumura D, Jain RK. 2002. Acidic extracellular pH induces vascular endothelial growth factor (VEGF) in human glioblastoma cells via ERK1/2 MAPK signaling pathway—Mechanism of low pH-induced VEGF. J Biol Chem 277:11368–11374.

Brown JM. 1999. The hypoxic cell: A target for selective cancer therapy—Eighteenth Bruce F. Cain Memorial Award lecture. Cancer Res 59:5863–5870

Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brussel- mans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E. 1998. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490

Helmlinger G, Schell A, Dellian M, Forbes NS, Jain RK. 2002. Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. Clin Cancer Res 8:1284–1291.

Pouyssegur J, Dayan F, Mazure NM. 2006. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441:437–443.

Vukovic V, Tannock IF. 1997. Influence of low pH on cytotoxicity of paclitaxel, mitoxantrone and topotecan. Br J Cancer 75:1167–1172.

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