Tumour Hypoxia

Tumour structure

Solid tumours require the availability of both oxygen and nutrients for sustained growth. These vital ingredients can only be provided if there is an adequate blood supply.

One of the characteristics of tumour cells is their ability to stimulate blood vessel development (angiogenesis). However, the vessels formed are of very poor quality which severely compromises the delivery of oxygen.

Consequently, tumours have significantly lower median oxygen levels compared to normal tissues (see table below).

Tumours have significantly lower median oxygen levels compared to normal tissues

Table comparing oxygen levels in different contexts

mm Hg % oxygen Context
760 100 Atmospheric pressure
160 21.1 Approx. level of oxygen in inspired air
107 14.1 Approx. level of oxygen in lung alveoli
40 5.3 Mid-range of oxygen levels in peripheral tissues
8.6 1.1 Mid-range of oxygen levels in solid tumors
30 3.9 Level in normal prostate [4]
6 0.8 LNCaP prostate tumour xenografts [5]
2 0.3 Level in human prostate tumours in situ [4]

Oxygen levels in tumours

Oxygen levels also vary throughout the tumour due to the intermittent opening and closing of inadequately-formed tumour blood vessels. This is especially true within the tumour core. Studies report mean oxygen levels between 3 and 19-fold lower than the associated normal tissue [1].

Cells that are able to survive in these hypoxic areas are also particularly resistant to treatment with many standard anticancer drugs. This is attributed to poor drug delivery (due to their distance from blood vessels) and/or lack of chemosensitivity (often found in these quiescent, although still viable, cells).

Hypoxia annotated

Tumor cells grouped around a capillary (1) showing viable cells (2). Hypoxic cells (3) lie at the outer edge close to the necrotic area (4). As oxygen is consumed by cells close to capillaries (1), the levels drop leaving outer cells (3) (beyond 70-150 microns – depending on tumor type) exposed to hypoxia or anoxia.

Most forms of radiotherapy are also less effective at very low oxygen levels as the cytotoxicity of ionising radiation is enhanced by the presence of oxygen [2].

Hypoxic cells are therefore very treatment resistant. In addition, the hypoxic microenvironment selects for cells that are more stress-resistant and malignant. This is of crucial importance since hypoxic cells can become reoxygenated during treatments that target and remove better-oxygenated cells; thus tumour regrowth occurs with cells that are more malignant and more metastatic [3].

Unfortunately, the development of more malignant, metastatic tumours is often the precursor to disease-related morbidity and ultimately the death of the patient. It is therefore imperative that a means be found to target and remove this hypoxic subpopulation, rather than allowing them to repopulate the tumour.

Targeting hypoxic cancer cells

Hypoxia selective cytotoxins (bioreductive drugs) are the only class of chemotherapy drug which can be used to specifically target hypoxic tumour cells. These drugs are by definition activated to cytotoxic compounds in a low oxygen environment (below approximately 2%).

One advantage of this approach is the specificity of hypoxia as a drug target, since normal tissues are designed to be adequately oxygenated with oxygen levels ranging in normal peripheral tissues between 3.9 and 6.8% oxygen (30 Ð 51.6 mmHg). Rarely (if ever) do they fall below 2% (15 mmHg) since normal physiological responses are designed to maintain tissue homeostasis including oxygenation within the normal range.

However, tissue homeostasis does not occur effectively in tumours, resulting in oxygen levels varying from 0.3 Ð 2.4% (2.4 Ð 18 mmHg). Indeed it is likely that oxygen levels fall still further during treatment with anti-angiogenic drugs and other cytotoxic agents [3].

The severe hypoxia found in tumors provides a unique opportunity to specifically kill these treatment-resistant malignant tumor cells while sparing the normal tissue.

Hypoxia in tumours provides a unique opportunity to develop novel Hypoxia Activated Prodrugs

References

  1. Brown JM, Wilson WR. Exploiting tumor hypoxia in cancer treatment. Nat Rev Cancer. 2004, 4:437-47.
  2. Hall and Giaccia. Radiobiology for the Radiologist 2006, 6thedition, Lippincott Williams & Wilkins, Philadelphia.
  3. DeClerck K, Elble RC. The role of hypoxia and acidosis in promoting metastasis and resistance to chemotherapy.  Front Biosci. 2010; 15: 213-25.
  4. Movsas B, Chapman DJ, Hanlon Al, Horwitz EM, Pinover WH, Greenberg RE, Stobbe C, Hanks GE. Hypoxia in human prostate carcinoma: an Eppendorf pO2 study.  Am J Clin Oncol 2001; 24: 458-61.
  5. Ming L, Byrne N, Camac S, Mitchell C, Ward C, Waugh D, McKeown S, Worthington J.  Androgen deprivation results in time-dependent hypoxia in LNCaP prostate tumors; informed scheduling of the bioreductive drug AQ4N improves treatment response. Int J Cancer. 2012 Aug 23. doi: 10.1002/ijc.27796. [Epub ahead of print]