Adipose microenvironment plays a direct role in the growth and spread of androgen-independent (castrate-resistant) prostate cancer

July 7, 2013, Featured in Cancer and Natural Medicines, 0 Comments

Adipose tissue (fat tissue) is currently recognized as an endocrine organ similar to thyroid and pancreas, due to their ability to secrete hormones such as leptin and estrogen and estrogen that could affect metabolism, inflammation and cancer progression. We now know that tumor growth is regulated by interactions between tumor and their tissue microenvironment, such as fibroblasts, immune cells and the extracellular matrix.

Adipose tissue secretes a variety of cytokines, referred to as adipokines. Most adipokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and leptin, are pro-inflammatory. One prominent exception is adiponectin, an anti-inflammatory and anti-cancer adipokine, which promotes insulin sensitization and protects cardiovascular tissue from ischemic injury. Pro-inflammatory adipokines can increase chronic low-grade inflammation in adipose tissue. Tumor-associated adipocytes (fat cells) also contribute to inflammation. Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis.

Like other cancers, adipose microenvironment is involved in signaling pathways that influence prostate cancer progression. Periprostatic adipose tissue (PPAT) surrounds the prostate and promotes prostate cancer cell growth and aggressiveness. Frequently, growing prostatic tumor cells extend beyond the prostatic organ towards this fat depot. Apparently tumor-PPAT interaction enhances the production of growth factors, adipokines (cytokines), chemokines, matrix metalloproteinases (MMPs), and inflammatory mediators, which eventually facilitates tumor growth and metastasis.

A recent study shows that prostate tumor cells command PPAT to produce several factors favorable to their growth and aggressiveness. The study results show that tumor-PPAT crosstalk enhances the production of the adipokines associated with prostate cancer progression (osteopontin, TNF-α, IL-6) and reduces the expression of adiponectin (an anti-inflammatory, anti-cancer adipokine). IL-6 is involved in the transition from an androgen-dependent to an androgen-independent phenotype. In androgen-independent phase, serum IL-6 shows a significant increase. IL-6 also promotes tumor angiogenesis by activating VEGF via STAT3. 

Strikingly, in this study, osteopontin protein expression was 13-fold upregulated by tumor-PPAT interaction. Osteopontin is an extracellular matrix protein, which promotes cell attachment, and cell migration. Osteopontin also stimulates expression of inflammatory cytokines such as IL-1, IL-6, and TNF-α by macrophages. Increased expression of osteopontin promotes tumor growth and spread. Additionally, osteopontin also plays an important role in biomineralization, osteoclast differentiation, and bone resorption. High plasma osteopontin is linked to tumor hypoxia, metastasis, and poor prognosis. Patients with metastatic androgen-independent (castrate-resistant) prostate cancer have significantly increased osteopontin values compared with localised prostate cancer. 

Obesity and prostate cancer: gene expression signature of human periprostatic adipose tissue.

Obesity-related systemic factors promote an invasive phenotype in prostate cancer cells. 

Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis.

Tumor cell-educated periprostatic adipose tissue acquires an aggressive cancer-promoting secretory profile.

Differential effects of leptin on the invasive potential of androgen-dependent and -independent prostate carcinoma cells.

Leptin and adiponectin interact in the regulation of prostate cancer cell growth via modulation of p53 and bcl-2 expression. 

Effects of adipocytes on the proliferation and differentiation of prostate cancer cells in a 3-D culture model.

Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells.

Interleukin-6: a multifunctional targetable cytokine in human prostate cancer.

Osteopontin is an activator of human adipose tissue macrophages and directly affects adipocyte function.

Role of the metastasis-promoting protein osteopontin in the tumour microenvironment.

Increased expression of osteopontin contributes to the progression of prostate cancer.

Role of osteopontin in adhesion, migration, cell survival and bone remodeling.

Pre- and post-translational regulation of osteopontin in cancer.

Plasma osteopontin as a biomarker of prostate cancer aggression: relationship to risk category and treatment response.

PPAT also produce and release pro-MMP9. Most MMP’s (matrix metalloproteinases) are secreted as inactive pro-proteins which are activated when cleaved by extracellular proteinases. MMP9 is the principle MMP although MMP2 is also expressed in prostate cancer cells. Proteins of MMP family are involved in multiple stages of cancer progression including the extracellular remodeling in tumor progression and metastases. Moreover, PPAT activates STAT-3 signaling to promote prostate cancer cell survival and migration. STAT-3 is critical for leptin signaling and its constitutive activity induces specific target genes that stimulate cell proliferation, prevent apoptosis, promote angiogenesis and facilitate tumor immune evasion.

Both osteopontin and MMP9 secreted by PPAT are also associated with angiogenesis via regulation of secretion of VEGF and angiostatin in androgen-independent (castrate-resistant) prostate cancer cells. Upregulation of secreted osteopontin and MMP9 correlated with an increase in tumor growth and angiogenesis compared to cells expressing low levels of osteopontin and MMP9. 

Matrix metalloproteinases and angiogenic factors: predictors of survival after radical prostatectomy for clinically organ-confined prostate cancer?

P21 activated kinase-1 (Pak1) promotes prostate tumor growth and microinvasion via inhibition of transforming growth factor β expression and enhanced matrix metalloproteinase 9 secretion.

Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro.

Periprostatic adipose tissue as a modulator of prostate cancer aggressiveness.

The multifaceted roles of osteopontin in cell signaling, tumor progression and angiogenesis.

Tumor cells often have characteristic changes through the acquisition of genetic and/or epigenetic alterations that provide adaptive advantages and the metastatic niche is remodeled. Most prostate cancers begin in an androgen-dependent state. However, over time, most tumors become androgen independent and no longer respond to hormonal therapies. Androgen-independent (castrate-resistant) prostate cancer is defined by disease progression despite androgen-deprivation therapy (ADT) and may present as one or any combination of a continuous rise in serum levels of PSA (prostate-specific antigen), progression of pre-existing disease, or appearance of new metastases.

The androgen receptor, a protein ignition switch for prostate cancer cell growth and division, is a master of adaptability. The shift from androgen-dependent to androgen-independent cell growth occurs, in part, because the androgen receptor switches on an entirely different set of genes in the latter group than in the former. HDAC6 (Histone deacetylase 6), a member of the HDAC family, regulates androgen receptor hypersensitivity and nuclear localization, mainly via modulating HSP90 (heat shock protein 90) acetylation.

Androgen-independent (castrate-resistant) tumor cells depend on growth factors, adipokines (cytokines), chemokines, MMPs, and inflammatory mediators secreted by tumor microenvironment for their growth and spread. Thus, prostate tumor can change its microenvironment, and the microenvironment can enhance tumor growth and spread. PPAT may play a direct role beyond being the “stimuli” or “fuel”. Clinically, we suggest that PPAT and HDAC6 might be novel targets for therapeutic intervention in prostate cancer, especially in patients with metastatic androgen-independent (castrate-resistant) prostate cancer. Zorvan inhibits the PPAT-mediated pathways and has been found to induce apoptosis of prostate cancer cells. Zorvan can also alternately interrupt the crosstalk between tumor and PPAT. The combined synergistic use of Zorvan and specific HDAC6 inhibitor is an effective method for controlling both androgen-dependent and androgen-dependent prostate cancer progression. You can take 40 mg Zorvan, 3-4 times per day for treatment of androgen-independent (castrate-resistant) prostate cancer.

Current management of castrate-resistant prostate cancer.

The changing landscape in the treatment of metastatic castration-resistant prostate cancer.

HDAC6 regulates androgen receptor hypersensitivity and nuclear localization via modulating Hsp90 acetylation in castration-resistant prostate cancer.

FOXA1 promotes tumor progression in prostate cancer and represents a novel hallmark of castration-resistant prostate cancer.

Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer.

FOXA1 mutations in hormone-dependent cancers.

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