Tumor hypoxia and therapeutic resistance

For many years, the identification of tumor hypoxia, its systematic characterization and the assessment of its clinical relevance were not possible due to the lack of methods suitable for the routine measurement of intratumoral oxygen tensions in patients. In the late 1980s, a novel and clinically applicable standardized procedure was established enabling the determination of tumor oxygenation in accessible primary tumors, local recurrences, and metastatic lesions in patients using a computerized polarographic needle electrode system (Vaupel et al. 1991; Hockel et al. 1991). Within a relatively short period of time, the significance of tumor oxygenation for therapy outcome became evident in…

Biological consequences of tumor hypoxia

Growing evidence from experimental and clinical studies points to the fundamental, pathophysiologic role of hypoxia in solid tumors. Intratumoral hypoxia is a consequence of a structurally and functionally disturbed microcirculation, with deterioration of the diffusion geometry and of tumor-associated anemia. Hypoxia-induced changes of the proteome in the neoplastic and stroma cells may lead to neoplastic growth impairment through molecular mechanisms, resulting in cellular quiescence, differentiation, and apoptosis. Alternatively, hypoxia-induced proteome changes activating nonspecific stress response, anaerobic metabolism, angiogenesis, tissue remodeling, and change of cell contacts may p…

Membrane-Bound F1 ATPase from Micrococcus Sp. ATCC 398E. Purification and Characterization by Affinity Chromatography

A chemically reactive ATP analogue, 6-[(3-carboxy-4-nitrophenyl)thio]-9-β-D-ribofuranosylpurine 5′-triphosphate (Nbs6ITP) has been synthesized. It has the ability to form stable thioether bonds between the 6-position of the purine ring and aliphatic mercapto groups. The nucleotide moiety of the reagent has been covalently bound to agarose, via iminobispropylamine and N-acetyl-homocysteine as spacer with the purpose of producing an affinity chromatography material. The affinity matrix binds solubilized F1 ATPase from a crude extract of Micrococcus sp. membranes. Afterwards the enzyme can be selectively eluted from the column at a defined ATP concentration. This method is superior to the conv…

Therapeutic Angiogenesis in Surgery and Oncology

The aim of this presentation is to demonstrate the pathological importance of microenvironmental tissue hypoxia and to elucidate a general treatment concept for this situation which we have termed therapeutic angiogenesis 1. Hypoxia not only represents an insufficient oxygen supply for the cells of a given tissue area but is also regarded as an indicator for their metabolic deprivation and the concomitant accumulation of waste products. Therapeutic angiogenesis applied either with clinically established methods or using novel ways, which are the objectives of laboratory research and clinical trials at present, or in so far hypothetical forms, should lead to an expansion of the functional mi…

Microregional expression of glucose transporter-1 and oxygenation status: lack of correlation in locally advanced cervical cancers.

Abstract Purpose: Glucose transporter-1 (GLUT-1), a target gene of hypoxia-inducible factor-1, has been considered a candidate endogenous marker of tumor hypoxia. Expression of GLUT-1 may also serve as an indicator for the induction of the transcriptional response to hypoxia, which has been linked to enhanced proliferation, resistance to therapy, and metastatic propagation of cancer cells. Overexpression of GLUT-1 has been shown to correlate with poor prognosis in several tumor entities, among them cancers of the uterine cervix. The validity of these hypotheses is investigated. Experimental Design: The expression of GLUT-1 was assessed in 80 biopsies of Eppendorf oxygenation measurement tra…

Detection and characterization of tumor hypoxia using pO2 histography.

Data from 125 studies describing the pretreatment oxygenation status as measured in the clinical setting using the computerized Eppendorf pO2 histography system have been compiled in this article. Tumor oxygenation is heterogeneous and severely compromised as compared to normal tissue. Hypoxia results from inadequate perfusion and diffusion within tumors and from a reduced O2 transport capacity in anemic patients. The development of tumor hypoxia is independent of a series of relevant tumor characteristics (e.g., clinical size, stage, histology, and grade) and various patient demographics. Overall median pO2 in cancers of the uterine cervix, head and neck, and breast is 10 mm Hg with the ov…

Lack of correlation between expression of HIF-1alpha protein and oxygenation status in identical tissue areas of squamous cell carcinomas of the uterine cervix.

Abstract Hypoxia inducible factor-1α (HIF-1α) has been proposed as a candidate endogenous marker of tumor hypoxia and as a molecular mediator of hypoxia-driven malignant progression and acquired treatment resistance. In this study, HIF-1α expression in 68 biopsies of oxygenation measurement tracks from squamous cell carcinomas of the uterine cervix of 38 patients was assessed. Expression of HIF-1α was commonly found to increase as a function of distance from microvessels, at the center of tumor cell aggregations, and in the vicinity of necrotic areas. However, there was no correlation of HIF-1α expression with median oxygen tension (oxygen partial pressure; pO2) and hypoxic fractions (hypox…

Lack of Hypoxic Response in Uterine Leiomyomas despite Severe Tissue Hypoxia

Abstract Hypoxia is now established as a key factor influencing the pathophysiology of malignant growth. Among other effects, hypoxia modulates the expression of a multitude of genes through the induction of hypoxia-inducible transcription factors. This differential gene expression favors angiogenesis, cell survival, an invasive/metastatic phenotype, and resistance to anticancer therapies. Because benign tumors do not exhibit these traits, one might expect these entities to be neither hypoxic nor to induce the genetic hypoxia response program. To test this hypothesis, an investigation of the oxygenation status of 17 leiomyomas and 1 leiomyosarcoma of the uterus using polarographic needle el…

Blood supply, oxygenation status and metabolic micromilieu of breast cancers: characterization and therapeutic relevance.

The metabolic microenvironment of a tumor is predominantly determined by the efficacy of blood flow, flux parameters (such as diffusion and convective currents in the interstitial space) and metabolic rates. The most important factors in this context include oxygen and nutrient supply, tissue pH and the bioenergetic status. It is now widely accepted that the metabolic microenvironment of a tumor can dramatically influence a range of factors such as proliferation rate, cell cycle position, growth rate and the development of apoptosis and necrosis. At the same time, these parameters can have an impact on tumor detection, therapeutic response to conventional irradiation, some chemotherapy agen…

Tumor Vascularity, Hypoxia, and Malignant Progression in Solid Neoplasms

Malignant progression designates the biologic process which transforms a phenotypically normal cell fixed and cooperating within a tissue into a disseminated therapy-resistant lethal disease. In clinical terms this process consists of three major steps (Fig. 1): () the transition from regulated to deregulated cell proliferation, () the emerging ability of the neoplastic cell collectives to induce angiogenesis and to invade other tissues, () the development of metastases and of resistance towards anti-tumor therapies.

Impact of oxygenation status and patient age on DNA content in cancers of the uterine cervix.

Abstract Purpose In carcinomas of the uterine cervix, the tumor oxygenation status has been shown to be a prognostic indicator that is independent of treatment modality. In vitro studies suggest gene amplification and polyploidization to be among the major consequences of hypoxia (with or without consecutive reoxygenation) and to be associated with treatment resistance and tumor progression. This study analyzed whether hypoxia alters net DNA content in uterine cervix cancer cells to the extent that it is identifiable by DNA image cytometry. Methods and materials In 64 patients with primary cervical cancer, tumor oxygenation was assessed polarographically and correlated with cell DNA content…

The Vascular Anatomy of the Inner Anterior Abdominal Wall with Special Reference to the Transversus and Rectus Abdominis Musculoperitoneal (TRAMP) Composite Flap for Vaginal Reconstruction

This study was designed to clarify the vascularization of the inner anterior abdominal wall with respect to the novel transversus and rectus abdominis musculoperitoneal (TRAMP) flap, which was introduced recently for vaginal reconstruction. A series of human cadavers was injected with a lead oxide-gelatine mixture by means of the deep inferior epigastric artery and subsequently dissected and examined by radiography. In all cases we found that the blood supply of the entire rectus abdominis muscle from the symphysis to the costal arch and that of the medial 10 to 15 cm of the transversus abdominis muscle, as well as the underlying peritoneum, was provided by several branches of the deep infe…

Five-year experience with combined operative and radiotherapeutic treatment of recurrent gynecologic tumors infiltrating the pelvic wall

BACKGROUND. Whereas 25 to 50% of selected patients with gynecologic tumors who relapse centrally in an irradiated pelvis can be salvaged by exenteration, postirradiation recurrence infiltrating the pelvic side wall generally has been fatal. We have designed the combined operative and radiotherapeutic treatment (CORT) procedure for the treatment of postirradiation recurrence infiltrating the pelvic wall and developed several new techniques for its realization. The aim of the surgery is as follows : (1) total resection of the tumor with only a microscopic margin (R1) at the pelvic wall, preserving the bony pelvis and the neurovascular support of the leg ; (2) modulation of the therapeutic ind…

Quantitative angiogenesis assays: progress and problems.

Different T-cell Receptor (TCR) Zeta Chain Expression in Cervical Cancer and its Precursor Lesions

OBJECTIVE Cervical cancer is associated with infection of epithelial cells with the human papillomavirus (HPV) type 16 and HPV18. A functional signalling machinery in T-cells is required in order to successfully fight and eradicate HPV16+ transformed epithelial cells. One of the key signalling molecules associated with the T-cell receptor (TCR) is the homodimeric zeta chain molecule. MATERIAL AND METHODS 28 formalin fixed und paraffin embedded samples of cervical tissue with cervical intraepithelial lesions CIN I (n = 3), CIN III (n = 7), invasive cervical carcinoma (CC) (n = 13) and normal cervical tissue (n = 5) has been evaluated for HPV-PCR und zeta chain immunohistochemistry. For immun…

Oxygenation Status of Gynecologic Tumors: What is the Optimal Hemoglobin Level?

Tumor hypoxia has been linked to the development of treatment resistance, tumor progression, and poor prognosis. Since anemia is a major causative factor for the development of hypoxia, the association between blood hemoglobin concentration (cHb) and tumor oxygenation was examined in this study.Pretreatment O(2) tension (pO(2)) measurements were performed in 59 primary carcinomas of the uterine cervix in which a stringent histopathologic examination of the electrode tracks was mandatory in order to exclude measurements in necrotic, stromal or normal cervical tissue. In addition, pO(2) readings in twelve primary cancers and 17 local recurrences of vulvar cancers were included in this study. …

Human papillomavirus (HPV) DNA in primary cervical cancer and in cancer free pelvic lymph nodes--correlation with clinico-pathological parameters and prognostic significance.

OBJECTIVE To assess whether the presence of human papilloma virus (HPV) DNA and/or several genotypes of HPV DNA in primary cervical cancer and cancer free pelvic lymph nodes are correlated with several clinicopathological parameters of well-defined prognostic significance and whether virological parameters are predictors of long-term survival in cancer patients. PATIENTS AND METHODS 223 cases of cervical cancer patients included in this retrospective study underwent follow-up evaluation. Survival and cause of death were examined for 204 (91.4%) patients, with a mean follow-up time of 4.4 years. HPV DNA was detected using the high sensitive polymerase chain reaction (PCR) method followed by …

Endogenous Hypoxia Markers: Case Not Proven!

The pivotal role of hypoxia within the pathophysiological framework of solid malignant tumors is now considered to be indisputable. The fact that hypoxia can cause resistance to various cancer therapies and promote malignant progression is reflected in its adverse impact on prognosis which is repeatedly shown for various tumor entities. Knowledge in this area is based on direct assessment of the oxygenation status using O2-sensitive microsensors. However, weaknesses of this standard method are its invasiveness and limitation to accessible tumor entities. Hypoxia-inducible factor (HIF)-1α, the master transcriptional regulator of the hypoxic response, as well as certain downstream genes, e.g.…

Relationship between hemoglobin levels and tumor oxygenation

Tissue hypoxia is a powerful and independent adverse prognostic factor in solid tumors. As outlined in Chapter 11, one major factor causing tumor hypoxia is a decreased O2 transport capacity of the blood resulting from tumor-associated and/or therapy-induced anemia, which is a frequent complication seen in cancer patients (Ludwig et al. 2004; Birgegard et al. 2005).

Oxygenation of Cervix Cancers: Impact of Clinical and Pathological Parameters

Current knowledge on the oxygenation status of carcinomas of the uterine cervix is mostly based on pretherapeutic data obtained in pre-and postmenopausal women. Mean and median 02 tensions (pO2) obtained from >20,000 p02-measurements in more than 400 squamous cell carcinomas of the uterine cervix observed by several research groups were, on average, distinctly lower than in normal tissues. Oxygen tensions measured in the normal cervix of nullipara patients revealed a median pO2 of 42 mmHg, whereas in conscious patients with locally advanced cancers of the cervix (stage FIGO lb-IVa), the median pO2 values were 10-20 mmHg. In patients under general propofol-anesthesia the median p02 values we…

Carbonic anhydrase IX expression and tumor oxygenation status do not correlate at the microregional level in locally advanced cancers of the uterine cervix.

Abstract Purpose: Carbonic anhydrase IX (CA IX) can be induced by hypoxia in vitro and shows an immunohistochemical expression pattern that is predominantly found in perinecrotic tumor areas and correlates with exogenous markers of hypoxia, such as pimonidazole. CA IX might therefore serve as an endogenous marker of tumor hypoxia, although comparisons of CA IX immunostaining with direct oxygenation measurements using pO2 microsensors have thus far yielded contradictory results. Experimental Design: Because tumor heterogeneity may be among the factors responsible for the discrepancy between the two methods, CA IX expression in tissue samples originating from oxygen microelectrode tracks of l…

The presence of HPV DNA in cervical cancer: correlation with clinico-pathologic parameters and prognostic significance: 10 years experience at the Department of Obstetrics and Gynecology of the Mainz University.

The objective of this study was to assess whether the presence of human papillomavirus (HPV) DNA and/or several genotypes of HPV DNA in cervical cancer are correlated with several clinicopathologic parameters of well-defined prognostic significance and whether virologic parameters are predictors of long-term survival in cancer patients. Two hundred twenty three cases of cervical cancer patients included in this retrospective study underwent follow-up evaluation. Survival and cause of death were examined for 204 (91.4%) patients, with a mean follow-up time of 4.4 years. HPV DNA was detected using the highly sensitive polymerase chain reaction (PCR) method followed by HPV DNA sequencing for H…

Expression of tenascin in human cervical cancer--association of tenascin expression with clinicopathological parameters.

Tenascin is an extracellular matrix glycoprotein, relevant for embryonal and fetal development, which is reexpressed in the stroma of benign and malignant tumors. Little is known about the molecular interaction of tenascin during neoplastic transformation and tumor progression in cervical cancer.We studied the expression of tenascin in normal tissue of the cervix uteri, cervical carcinoma in situ, and invasive cervical carcinoma in paraffin sections by immunohistochemistry using a monoclonal antibody. Tenascin immunoreactivity was compared with various prognostic parameters.In normal cervical tissue (n = 5) and in cervical carcinoma in situ (n = 10) only vessel walls showed a weak tenascin …

Tumor Vascularity—A Novel Prognostic Factor in Advanced Cervical Carcinoma

Objective: In the search for the optimal treatment of advanced cervical cancer, the identification of valid prognostic factors obtainable without histopathologic investigation of the entire tumor and the locoregional lymph nodes is of paramount interest. Tumor microvessel density has recently been demonstrated to correlate strongly with disease aggressiveness in breast cancer and other malignancies. Methods: We established a computerized image analysis system to quantify tumor microvascularity by using the closest-individual method, which determines the distribution of distances from random points within the tumor to the closest microvessel (DTCMV). Tumor microvascularity was assessed in pa…

Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy.

Hypoxic areas are a characteristic property of solid tumors. Hypoxia results from an imbalance between the supply and consumption of oxygen. Major pathogenetic mechanisms for the emergence of hypoxia are (1) structural and functional abnormalities in the tumor microvasculature; (2) an increase in diffusion distances; and (3) tumor- or therapy-associated anemia leading to a reduced O2 transport capacity of the blood. There is pronounced intertumor variability in the extent of hypoxia, which is independent of clinical size, stage, histopathologic type, and grade. Local recurrences have a higher hypoxic fraction than primary tumors. Tumor hypoxia is intensified in anemic patients, especially i…

Tumor Oxygenation and Tumor Vascularity: Evidence for Their Clinical Relevance in Cancer of the Uterine Cervix and Considerations on Their Potential Biological Role in Tumor Progression

Most solid malignancies are thought to be derived from a single neoplastic precursor cell having lost proliferation control and gained the ability to penetrate basement membranes and to invade into the stroma. During the disease course tumors increase their overall cell number by local expansion and the development of regional and distant metastases. Along with the increase in cell number the tumors loose hormonal or other external signal dependencies and acquire resistances towards radio— and chemotherapy. The progressing disease causes symptoms through impaired tissue/organ functions and complications, and finally kills the individual (unless other causes leading to death become manifest …

Myoperitoneale Composite Flaps: Ein neues operatives Prinzip zur Vaginalrekonstruktion

In spite of the development of various techniques for the formation of a neovagina, the longterm results are often disappointing, especially if the simpler methods (dilation, ectopic pouch formation, epithelium transfer) have been applied. The more complex surgical techniques such as musculo/fasciocutaneous and colon flaps are associated with a significant risk of severe complications. For certain operative situations necessitating vaginal reconstruction, adequate procedures are still missing. Based on surgico-anatomic investigation of the vascular territories of the myoperitoneal anterior abdominal wall, we introduce the use of myoperitoneal composite flaps from the deep inferior epigastri…

Tumor Oxygenation and Its Relevance to Tumor Physiology and Treatment

For many years, the identification of tumor hypoxia, its systematic characterization and the assessment of its clinical relevance were not possible due to lack of methods suitable for the routine measurement of intratumoral oxygen tensions in patients. In the late 1980s, a novel and clinically applicable standardized procedure was established enabling the determination of the tissue oxygenation status in primary tumors, local recurrences, and metastatic lesions in patients using a computerized polarographic needle electrode system. Within a relatively short period of time, the significance of tumor oxygenation for therapy outcome became evident in numerous experimental and clinical studies.

The combined operative and radiotherapeutic treatment (CORT) of recurrent tumors infiltrating the pelvic wall: First experience with 18 patients

CORT is a new radiosurgical treatment concept for patients with recurrent gynecologic malignancies infiltrating the pelvic wall. The operative part consists of (i) staging laparotomy; (ii) maximum debulking of the tumor from the pelvic wall and exenteration of infiltrated central pelvic organs; (iii) implantation of brachytherapy guiding tubes on the residual tumor/tumor bed at the pelvic wall; (iv) pelvic wall plasty with muscle and omentum flaps to create a protective distance between the tubes and the pelvic hollow organs and to induce therapeutic angiogenesis; and (v) surgical reconstruction of bowel, bladder, and vulvoperineovaginal functions. Radiation is given postoperatively as frac…

Intratumoral PO2 Histography as Predictive Assay in Advanced Cancer of the Uterine Cervix

Experimental evidence suggests that the hypoxic fraction in a solid tumor may increase its malignant potential and reduce its sensitivity towards nonsurgical treatment modalities such as standard irradiation and certain anticancer agents1–5. However, the clinical importance of tumor hypoxia remains uncertain since valid methods for the routine measurement of intratumoral O2-tensions in patients have so far been lacking.

Tumor hypoxia in pelvic recurrences of cervical cancer.

We have previously demonstrated in primary cancer of the uterine cervix that tumor hypoxia, as determined polarographically, is strongly associated with clinical malignant progression of the disease. Having applied a similar methodological approach to investigate loco-regional relapses, we found a pronounced shift to more hypoxic oxygenation profiles in the recurrent tumors than in the primary tumors. Median pO2 values in 53 pelvic recurrences were significantly lower than the median pO2 values of 117 primary tumors of comparable sizes (7.1 +/- 1.1 mmHg vs. 12.1 +/- 1.0 mmHg, p = 0.0013). The differences in tumor oxygenation between primary and recurrent tumors mirrored the differences in t…

GLUT-1 staining of squamous cell carcinomas of the uterine cervix identifies a novel element of invasion.

Perturbation of the normal tissue architecture in solid malignant tumors is perceived to be the consequence of actively migrating cancer cells which invade the adjacent normal host tissue. The opposite, invasion of cancer cell clusters by a vascularized stroma, has not been considered. The latter process should, however, be expected to occur since the hypoxic cores of tumor cell aggregates, under the control of HIF-1, are known to secrete cytokines (e.g., bFGF, VEGF) which attract fibroblasts and induce blood vessel formation. In this study, the expression of glucose transporter (GLUT)-1, a major HIF-1 target gene, was examined in 51 squamous cell carcinomas of the uterine cervix by immunoh…

Evidence for and Against Hypoxia as the Primary Cause of Tumor Aggressiveness

In clinical trials, tumor hypoxia has consistently been associated with tumor aggressiveness. The evidence for an association between hypoxia and metastasis and more rapid tumor progression and death is seen in uterine cervical cancer, and sarcoma of soft tissue. Evidence is building in prostate, vulva, head and neck, and breast cancers. A major question is whether hypoxia precedes tumor aggressiveness or whether aggressive tumors incidentally are also hypoxic.

Are pelvic side-wall recurrences of cervical cancer biologically different from central relapses?

Background. By using the Combined Operative and Radiotherapeutic Treatment (CORT) procedure, pelvic side-wall recurrences of gynecologic malignancies arising in a previously irradiated pelvis may be locally controlled. Local control of central relapses may be achieved by exenteration alone. If, in cervical cancer, both relapse patterns are biologically different (as hypothesized by some investigators), distinct disease courses after local treatment may be expected. Methods. Since June, 1989, 32 pelvic recurrences of cervical cancer were treated for local control in this institution. The median size of the recurrent tumors was 5 cm (range, 2–9 cm); 84% of the patients had been extensively ir…

Hypoxia and radiation response in human tumors

This study demonstrates by an updated analysis of an ongoing prospective study that tumor oxygenation, as measured with a validated standardized polarographic needle electrode method before treatment, powerfully predicts the prognosis of patients receiving radiotherapy for intermediate and advanced stage cancer of the uterine cervix. First evidence for a host component in tumor oxygenation based on a significant correlation between median pO 2 values determined in normal subcutaneous fatty tissue and in cervical cancer is also presented. Further investigations are necessary to clarify whether tumor hypoxia is just a marker of intrinsic tumor aggressiveness or whether the negative impact of …

Tumor oxygenation: a new predictive parameter in locally advanced cancer of the uterine cervix.

Abstract Experimental evidence suggests that hypoxia may increase the malignant potential and reduce the sensitivity toward nonsurgical treatment modalities in solid rodent tumors. However, the importance of tumor hypoxia in human malignancies is still uncertain. We have developed a clinically applicable standardized procedure for the determination of intratumoral p O 2 in advanced cervical cancers by use of a computerized polarographic needle electrode histograph. To evaluate the significance of tumor oxygenation as a new oncologic parameter we initiated an open prospective clinical trial at the University of Mainz Medical Center in June 1989. Until October 1992 50 patients with advanced c…

F1-ATPase from Micrococcus sp. ATCC 398. Purification by Ion-Exchange Chromatography and Further Characterization. (Auto)proteolysis and Dissociative Effects

The preparation of highly purified F1-ATPase from Micrococcus sp. ATCC 398 by application of DEAE-Sepharose CL-6B chromatography as final step is described. This enzyme consists of five subunits of different molecular weight: alpha (65000), beta (55000),gamma (35000), delta (20000), and epsilon (17000). Disc electrophoresis on 5% polyacrylamide gels removes the epsilon-polypeptide yielding an active ATPase complex with four different subunits: alpha, beta, gamma, delta. Additionally, by variation of the ionic strength delta can (partly) removed allowing the isolation by disc electrophoresis of an active ATPase complex which consists only of three different subunits alpha, beta, and gamma. I…

How to Improve the Uterotomy Healing

Abstract Suboptimal uterotomy healing following cesarean delivery or metroplastic operations may lead to considerable complications. New insights in the biology of wound healing and the availability of a variety of biologic response modifiers open the possibility to modulate the process of wound healing in order to gain clinical benefits. Can uterotomy healing be improved by local application of biosubstances? We developed an uterotomy model in the rat and measured the bursting pressure at defined times postwounding as a functional parameter of wound healing. In addition, the healing process was assessed by serial light microscopic histology. Uterotomy healing was investigated in the presen…

Tumor Hypoxia and Malignant Progression

Publisher Summary This chapter discusses tumor hypoxia and malignant progression. Hypoxic (or anoxic) areas arise as a result of an imbalance between the supply and the consumption of oxygen. Whereas in normal tissues or organs the O2 supply matches the metabolic requirements, in locally advanced solid tumors the O2 consumption rate of neoplastic as well as stromal cells may outweigh an insufficient oxygen supply and result in the development of tissue areas with very low O2 levels. Major pathogenetic mechanisms involved in the emergence of hypoxia in solid tumors are (a) severe structural and functional abnormalities of the tumor microvessels (b) a deterioration of the diffusion geometry, …

Hypoxia in Breast Cancer: Pathogenesis, Characterization and Biological/Therapeutic Implications

Nearly 50% of locally advanced breast cancers exhibit hypoxic and/or anoxic tissue areas that are heterogeneously distributed within the tumour mass. Hypoxia is predominantly caused by structural and functional abnormalities of the newly formed tumour vessels arising from neovascularization, by a disturbed microcirculation, by enlarged diffusion distances, and by tumour-associated or therapy-induced anaemia. The extent of pretherapeutically measured hypoxic tissue areas is independent of clinical tumour size and stage, and histological type and grade. Anaemia can substantially worsen tumour O2 depletion. Hypoxia is known to directly or indirectly confer resistance to irradiation and some ch…