Trends in Cell Biology
Volume 25, Issue 4, April 2015, Pages 234-240
Journal home page for Trends in Cell Biology

Review
Special Issue: Cell Biology of Cancer
Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance

https://doi.org/10.1016/j.tcb.2014.12.006Get rights and content

Highlights

  • Integrins contribute to cancer progression via adhesion-dependent and -independent pathways.

  • Specific integrins not only represent stem cell markers, but also dictate stem cell behavior.

  • Integrins drive therapeutic resistance through canonical and non-canonical mechanisms.

  • Integrin expression contributes to multiple steps of the metastatic cascade.

Interactions between cancer cells and their surroundings can trigger essential signaling cues that determine cell fate and influence the evolution of the malignant phenotype. As the primary receptors involved in cell–matrix adhesion, integrins present on the surface of tumor and stromal cells have a profound impact on the ability to survive in specific locations, but in some cases, these receptors can also function in the absence of ligand binding to promote stemness and survival in the presence of environmental and therapeutic stresses. Understanding how integrin expression and function is regulated in this context will enable the development of new therapeutic approaches to sensitize tumors to therapy and suppress their metastatic phenotype.

Section snippets

Integrin heterodimers and ligand specificity in cancer

When the extracellular matrix (ECM) is proteolytically degraded or deformed by mechanical forces, cells are prompted to undergo responsive changes that influence remodeling during physiological and pathological events. Integrins are a family of heterodimeric cell surface receptors that sense these changes and trigger a range of cellular responses by forming a physical connection between the inside and outside of a cell to allow the bidirectional ‘integration’ of signals to control cell

Dissecting integrin-dependent regulation of stem cells

Although epithelial stem cells play a critical role in the physiological development, maintenance, and remodeling of organs and tissues [17], their properties are also associated with the initiation and progression of carcinomas [18]. Since the stem cell niche is tightly regulated by signals from the local microenvironment including the ECM, certain integrins may be critical for the ability of stem cells to sense and respond to these cues in both normal tissues and cancer. Indeed, a number of

Connecting integrins and drug resistance

Despite advances in cancer treatment, many cancer therapies are limited by the development of resistance that results from a variety of factors, including alterations in the drug target, activation of prosurvival pathways, and ineffective induction of cell death. Resistance to anticancer therapeutics can be divided into two categories: intrinsic resistance derived from genetic or environmental factors pre-existing in the tumor, or acquired resistance resulting from adaptive responses,

Critical roles for integrins during the metastatic cascade

Metastasis is a multistep process that requires a cancer cell to escape from the primary tumor, survive in the circulation, colonize distant sites, and proliferate. Since integrin function can enable and enhance many facets of these steps, it is not surprising that increased expression of certain integrins within the primary tumor are associated with poor prognosis and enhanced metastasis in a variety of cancers [1] (Figure 3). This increased expression may reflect higher numbers of CSCs with

Concluding remarks

Recent findings have demonstrated that integrins participate in the regulation of stem-cell and cancer stem-cell biology and are required for cancer progression and drug resistance (Figure 3). Further understanding of which specific integrins are required for these events, whether these integrins are interchangeable or specifically required, whether these integrins define a subset of cells that expand in response to changes in the microenvironment, or whether a dynamic program allows the cells

References (66)

  • H.L. Goel

    Regulated splicing of the alpha6 integrin cytoplasmic domain determines the fate of breast cancer stem cells

    Cell Rep.

    (2014)
  • G. Mouneimne

    Differential remodeling of actin cytoskeleton architecture by profilin isoforms leads to distinct effects on cell migration and invasion

    Cancer Cell

    (2012)
  • A.M. Schooley

    beta1 integrin is required for anchorage-independent growth and invasion of tumor cells in a context dependent manner

    Cancer Lett.

    (2012)
  • M. Esposito et al.

    Targeting tumor-stromal interactions in bone metastasis

    Pharmacol. Ther.

    (2014)
  • J.S. Desgrosellier et al.

    Integrins in cancer: biological implications and therapeutic opportunities

    Nat. Rev. Cancer

    (2010)
  • J.K. Mouw

    Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression

    Nat. Med.

    (2014)
  • S.J. Shattil

    The final steps of integrin activation: the end game

    Nat. Rev. Mol. Cell Biol.

    (2010)
  • M. Barczyk

    Integrins

    Cell Tissue. Res.

    (2010)
  • M. Huang

    EGFR-dependent pancreatic carcinoma cell metastasis through Rap1 activation

    Oncogene

    (2012)
  • H.L. Goel et al.

    Enhancing integrin function by VEGF/neuropilin signaling: implications for tumor biology

    Cell Adhes. Migrat.

    (2012)
  • J.D. Hood

    Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis

    J. Cell Biol.

    (2003)
  • W. Guo et al.

    Integrin signalling during tumour progression

    Nat. Rev. Mol. Cell Biol.

    (2004)
  • E.M. Morse

    Integrin cytoplasmic tail interactions

    Biochemistry

    (2014)
  • N.E. Reticker-Flynn

    A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis

    Nat. Commun.

    (2012)
  • Y.L. Hsu

    Galectin-1 promotes lung cancer tumor metastasis by potentiating integrin alpha6beta4 and Notch1/Jagged2 signaling pathway

    Carcinogenesis

    (2013)
  • L. Seguin

    An integrin beta(3)-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition

    Nat. Cell Biol.

    (2014)
  • S. Charrin

    Tetraspanins at a glance

    J. Cell Sci.

    (2014)
  • H. Wang

    Tspan8, CD44v6 and alpha6beta4 are biomarkers of migrating pancreatic cancer-initiating cells

    Int. J. Cancer

    (2013)
  • C. Blanpain et al.

    Stem cell plasticity. Plasticity of epithelial stem cells in tissue regeneration

    Science

    (2014)
  • I. Malanchi

    Interactions between cancer stem cells and their niche govern metastatic colonization

    Nature

    (2012)
  • T. Oskarsson

    Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs

    Nat. Med.

    (2011)
  • I. Taddei

    Beta1 integrin deletion from the basal compartment of the mammary epithelium affects stem cells

    Nat. Cell Biol.

    (2008)
  • E. Rognoni

    Kindlin-1 controls Wnt and TGF-beta availability to regulate cutaneous stem cell proliferation

    Nat. Med.

    (2014)
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