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  • br ECM cancer and metastasis For

    2019-05-16


    ECM, cancer and metastasis For adiponectin receptor to become cancerous they must acquire the ability to survive, grow and invade leading to malignant transformation, tumour formation and ultimately overt secondary metastasis. Abnormal ECM can promote these abilities and is a well-documented hallmark of cancer. In fact, it has also been shown that aberrant ECM can precede malignant transformation in many tissues [3]. In addition, many ECM components and their receptors are overexpressed by cancer cells which typically leads to abnormal ECM that may potentiate the oncogenic effect of various growth factors, including ones known to be fundamental in bone remodelling, such as VEGF, IGF-1 and TGF-??. Whether these events occur concomitantly or one proceeds the other is much like asking which came first came first the chicken (ECM) or the egg (cancer)! It would be interesting to gain further insight into the nature and indeed timing of these changes, as well as understanding similarities and differences in the changes within the ECM and the cancer cells themselves. Physiological changes in the external environment of the tumour, such as hypoxia can also lead to changes in the ECM due to increased expression of enzymes responsible for the post-translational modification of collagen and other ECM components. This includes the lysyl oxidase (LOX) family of extracellular amine oxidases whose primary function is to post-translationally modify collagens and elastin in the ECM, thereby catalysing the covalent crosslinking of collagen fibres increasing stiffness and tensile strength. The increased stiffness of the ECM is “sensed” by the cancer cells which in turn focus their activities towards invasion, as opposed to proliferation, and drives them to migrate to distant metastatic sites. Consistent with this, the LOX enzyme was shown to be associated with lower distant metastasis-free survival and overall survival in breast cancer patients with ER-negative tumours, and also in head and neck cancer patients [5]. Expression of another LOX family member, LOX Like protein-2 (LOXL-2) was similarly shown to be correlated with metastasis and decreased survival in patients with aggressive breast cancer. Although not required for primary tumour growth, LOXL-2 was required for metastatic colonisation and metastatic growth in vivo. Mechanistically, LOXL-2 was shown to regulate the expression and activity of other ECM modifying proteins including tissue inhibitor of metalloproteinase-1 (TIMP1) and matrix metalloproteinase-9 (MMP9), key proteins involved in ECM remodelling [6]. Targeting of LOXL-2 with an inhibitory monoclonal antibody (AB0023) was also shown to be efficacious in both primary and metastatic xenograft models of cancer [7]. Further evidence that the LOX proteins can induce changes in the tumours ECM\'s physical properties to facilitate metastasis was provided more recently with the observation that LOX-mediated collagen crosslinking creates a growth-permissive fibrotic microenvironment capable of supporting metastatic growth by enhancing tumour cell persistence and survival [8]. Strikingly, not only do LOX enzymes modulate the ECM of the primary tumour, but they can also modulate the ECM of distant organs to form the pre-metastatic “niche” prior to the arrival of tumour cells and development of metastases [9]. The exact mechanisms behind this niche formation are not known; do tumour-derived factors circulate the body and exert differing effects on ECM remodelling within different organs, or do particular tumour-secreted factors initiate specific cascade reactions and signalling events in specific tissues? Pertinent to this review, the ability of these enzymes to modulate the ECM in the bone to facilitate bone metastasis is only now just being recognised [10].
    ECM and bone metastasis When considering the constituents of the ECM, as well as the molecular pathways involved in the dysregulation of the ECM that leads to oncogenic transformation, the similarity and overlap with the constituents of bone and the pathways involved in its homeostasis and remodelling are obvious. Bone is adiponectin receptor the largest “organised mesh” (by mass) in the human body – providing the ultimate scaffold that dictates the human form and ultimately function. Bone, like any other ECM, consists of fibrous proteins, predominantly type I collagen, and non-collagenous proteins such as proteoglycans, and glycoproteins such as osteopontin and fibronectin. The fact that many cancers have a predilection to metastasise to bone should perhaps not be so surprising then. However, unlike other ECMs bone is physiologically mineralized (thus 100,000–1,000,000 times stiffer than other tissues such as breast tissue). Bone is constantly remodelled throughout life, continually synthesizing osteoid – the unmineralised collagenous matrix which makes up about 50% of the bone\'s volume. These two properties should in theory preclude and facilitate invasion of cancer cells in the bone respectively, yet this appears not to be so. Stephen Paget first proposed the “seed and soil” hypothesis back in 1889 [11], this seminal paper and the resultant century or more of research has led to concept of the “bone and cancer vicious cycle” whereby once cancer cells arrive in the bone they release factors that stimulate osteoclastic bone resorption (IL-6, IL-8, MMPs TIMPS etc). This bone resorption causes the release of bone stored factors (in particular TGF-β) that favour the growth of the tumour in bone, which inevitably stimulates more osteoclastic bone destruction, and so on. Significant advances in identifying key players in the vicious cycle have been made in the last decade, with many attempts to prevent bone metastasis being focused on targeting this vicious cycle.